The nominees are polar opposites in their public demeanor and campaign styles -- and each has their share of vulnerabilities that they will have to overcome in the next five months.
Perhaps the most striking feature of the race is the candidates' historically high unfavorable ratings. According to a recent Washington Post/ABC News poll, 57% of registered voters said they had unfavorable views of both Clinton and Trump.
"It's a very unique situation, certainly not one that we've encountered recently in American politics, where voters are to a certain extent basically deciding who they least dislike," said Pennsylvania GOP strategist Mark Harris.
Here are some of the top challenges Clinton and Trump are likely to confront in the lead-up to November:
Lack of political discipline
Trump's hard-charging, controversial rhetoric helped him navigate the field of 17 candidates in the GOP primary but leaves him at risk of losing the general election.
His proposal to ban Muslims, questioning the heroism of Sen. John McCain, and suggesting a federal judge is biased against him due to his Mexican heritage, among others, will be replayed over and over and over again for the next five months.
Trump prides himself in being an "unpredictable" candidate, but his penchant for saying anything at any time could work against him -- as demonstrated by the growing firestorm among many Republicans in Washington over his comments regarding Judge Gonzalo Curiel.
"The presidency almost every cycle ultimately comes down to the trust and confidence of the American people and do they trust you to have the character and the demeanor to be the President of the Untied States? And right now, I think that very important indicator is an unknown with Trump," said Nevada strategist Peter Ernaut. "If I was his adviser, I would work on toning that message down a little bit -- actually, probably a lot."
But time and again, Trump has made it clear a new Trump isn't in the cards.
"You think I'm going to change? I'm not going to change," Trump said last week at a news conference in which he attacked the media for asking questions about the state of pledged donations to veterans groups.
Trump has also repeatedly offended another key general election demographic: women -- both before and while running for president.
Before he launched his campaign, he used words like "fat pig," "slob" and "dog" to insult women he disagreed with. And he participated in crude segments on shock jock Howard Stern's radio show, including ones in which Trump rated women on a 1-10 scale, noted that "a person who is flat-chested is very hard to be a 10" and explained his sexual proclivities.
And while running for president, he leveled misogynistic attacks at his fellow Republican presidential candidate Carly Fiorina -- suggesting she was too ugly to be elected -- and Fox News anchor Megyn Kelly, whom Trump referred to as a "bimbo" and suggested her tough questioning during the first GOP debate was tied to her menstrual cycle.
Trump has sought to make inroads with women, vowing that he will "cherish" and "protect" women like no other president, while pointing to the success of his daughter, Ivanka, and the women he's put in top positions at his company.
Still, his tawdry past coupled with Clinton's appeal as potentially the first woman president will make for an uphill climb as Trump looks to narrow the deficit he faces with women voters.
Trump long ago threw the Republican National Committee's 2012 autopsy report out the window. That report underlined the need for the party to be more engaging and inclusive of minority communities, notably Hispanics and African-Americans. Beyond policies and proposals, the party needed to adjust its tone, the report said.
And then Trump launched his campaign by calling undocumented Mexican immigrants criminals and "rapists," vowing to build a massive border wall and pledging to deport all estimated 11 million undocumented immigrants living in the U.S.
With the nomination now clinched, the wildly successful appeal of Trump's ideas and rhetoric could be Trump's downfall as he faces the larger and more diverse sea of general election voters -- and minority voters who are crucial voting blocks in battleground and some Republican-leaning states.
"States that have traditionally leaned Republican in the west like Colorado, New Mexico, are now heavily in the Democratic column because Mr. Trump has been so polarizing to Latinos. A lot of states -- even Arizona, looks like it could be leaning Democratic," said Steve Westly, a former California state controller and Democratic fundraiser supporting Clinton.
Trump's more establishment allies -- including his own campaign chairman Paul Manafort -- have hinted at an evolution in both policy and tone, one that would pull Trump along the path to moderation and broader appeal to minority communities. But that doesn't appear forthcoming.
A bare-bones campaign
It takes a village to win a presidential election. Trump, however, seems unfazed by the idea of waging his battle against Clinton with a bare-bones operation.
For most of the primary season, the Trump operation was notably insular, with campaign manger Corey Lewandowski serving as Trump's primary political strategist and spokeswoman Hope Hicks playing the role of sole media point of contact.
Although Trump has since appointed Manafort as campaign chairman, begun to build out a national finance team and hired several notable veteran Republicans, his campaign remains unusually small -- especially in contrast with Clinton's deep bench of staffers at every level of her campaign.
Trump indicated Monday that this is exactly how he likes it.
"I am getting bad marks from certain pundits because I have a small campaign staff. But small is good, flexible, save money and number one!" he tweeted.
The danger to Trump was demonstrated recently when comments Trump made in 2006 and 2007 regarding a housing crisis surfaced in multiple news outlets. The Clinton campaign pounced, producing a series of videos highlighting the comments as they looked to define Trump as a heartless, self-interested billionaire.
The bare-bones approach didn't hurt Trump in the primary, where he masterfully dominated the airwaves and made himself more accessible to reporters than any other candidate. But a general election race is something else entirely. The ring of Democratic super PACs have amped up their efforts to plant damaging stories about Trump in news reports since Trump clinched the nomination in May and the Clinton campaign's rapid response operation has capitalized on the reports.
While the Clinton campaign boasts a communications staff of more than a dozen, only one Trump campaign staffer, campaign spokeswoman Hicks, who is new to politics, handles media inquiries and sends out statements. It's a communications operation that frequently forces reporters to simply note that the campaign declined to comment, rather than inserting a traditional rebuttal.
In a demonstration of Trump's hands-on approach, the candidate himself conducted a call with surrogates on Monday, instructing them to forcefully push back on critics and members of the media on the Curiel uproar — and to keep criticizing the U.S.-born judge.
Meanwhile, internal rifts have also proved to be an unwelcome distraction. Last month, Trump abruptly parted ways with political director Rick Wiley, only weeks after he had started the job. Sources say there are ongoing tensions between Manafort and Lewandowski, as they angle for influence over the candidate.
'I'm not a natural politician'
Clinton is first to acknowledge that she's not a natural on the stump.
"I am not a natural politician, in case you haven't noticed, like my husband or President Obama," Clinton said at a Democratic debate in March. "I just have to do the best I can, get the results I can, make a difference in people's lives and hope that people see that I am fighting for them and that I can improve conditions economically and in other ways."
Republicans believe that among Trump's potential advantages against Clinton is his ability to excite voters, coupled with his knack for owning the media cycle. Trump has said the core to his general election strategy is high turnout and support from voters who are usually not inclined to participate in the political process.
Winning over Bernie supporters
Clinton is now the presumptive Democratic nominee, but she still needs to get her party in line.
Her fight against Sanders was more drawn out and contentious than most had originally expected. Although Sanders kicked off his unlikely campaign with a vow to never go after Clinton personally, his attacks grew increasingly sharp. Not only has the Vermont senator put Clinton on the spot on issues important to progressives like campaign finance reform and environmental protection, he has also pointed to her past decisions to accuse her of lacking the "judgment" to be president.
Sanders was able to win young voters -- including young women -- by significant margins over Clinton. She will have to remedy this by November.
Trump has repeatedly said that he believes he can win over some Sanders loyalists because the two candidates share a similar vision.
"You see blue-collar people in some of these states that voted for Bernie said they will vote for Trump before Hillary," said John Burton, chairman of the California Democratic Party. "That's very scary and that's what she's got to lay out what she's about and what she's going to do to bring these people out to vote."
Facing Trump's attacks
Jeb Bush was "low energy." Marco Rubio was "Little Marco." Ted Cruz was "Lyin' Ted."
Now, Trump has dubbed Clinton "Crooked Hillary."
But Trump's highly effective name-calling isn't all Clinton should be worried about as she faces Trump one-on-one.
Why? Because Trump will attack Clinton like no other Republican would.
Already, the presumptive GOP nominee has raised issues beyond the garden variety of Republican attacks against Clinton (Benghazi, emails etc...) and injected scandals that marred the administration of President Bill Clinton in the 1990s.
Trump has already raised the former president's marital infidelity and decades-old allegations of sexual assault, all while accusing Hillary Clinton of being a "nasty, mean enabler." He has also hinted at plans
to raise the Whitewater real estate scandal dating back to the 1970s.
And it won't just be Trump: a newly-launched pro-Trump super PAC with ties to the billionaire cut its first ad last week interspersing Clinton's defense of her email use with Clinton's untruthful denial that he had sexual relations with Monica Lewinsky.
But it's not just the subject matter.
As the 17 primary opponents Trump faced proved, the brash billionaire's unconventional style of attack can be particularly slippery to pin down.
Those who sought to rise above Trump's mudslinging, failed. Those who jumped right into the pit with Trump, also failed.
Clinton so far has ignored most of Trump's daily and most gutter-worthy attacks, instead mounting sustained assaults to hit Trump over singular issues -- first his comments about the 2008 financial crisis, then his news conference on donations to veterans' charities, and now Trump's comments about the Mexican-American judge presiding over his Trump University case.
Clinton's trust problem
The majority of Americans do not believe Clinton is honest and trustworthy. That's a big problem.
According to a recent New York Times/CBS survey, almost two-thirds, 64%, of registered voters do not believe Clinton is "honest and trustworthy." A Quinnipiac survey showed that more voters consider Trump to be honest and trustworthy than Clinton, 44% to 39%.
Clinton's use of a private email server during her tenure the State Department continues to dog her campaign and public image. The former secretary of state has insisted that she only used a non-government server after obtaining proper approval. But that line of defense was undermined after a State Department Inspector General report last month ruled that Clinton failed inform necessary State Department officials about her use of the private server, and that she also failed to surrender all government-related emails before leaving office.
About half of Americans said in a March CNN/ORC poll that Clinton's use of the private server was either a very or somewhat serious problem.
Last week, Trump even went as far as to say that Clinton should be imprisoned for the controversy surrounding her use of a private email server at the State Department.
"Hillary Clinton has got to go to jail," Trump said. "Folks, honestly. She's guilty as hell."