Washington (CNN) -- Sen. Jon Kyl, R-Arizona, the second ranking Republican in the Senate, announced Thursday he will not seek a fourth Senate term in 2012.
"There comes a time when you have to consider other things" to do, Kyl said at a news conference in Phoenix.
"There is more to life than working in the United States Senate," Kyl said, insisting his health is good and he could have won re-election if he tried. "My heart says it's time."
Kyl is the fifth senator to announce he will leave the Senate after next year. His departure will leave vacant a powerful spot in the Senate GOP leadership, and could lead to a scramble among a number of Republicans.
The move opens new speculation about the future of Sen. John Thune, R-South Dakota. Thune is contemplating a run for president, but now has the chance to move up and take Kyl's leadership position -- assistant Republican leader -- if he decides to stay. A Thune source told CNN he will make his decision by the end of this month.
Meantime, a source close to Tennessee Sen. Lamar Alexander, currently the third-ranking Republican, said Alexander will seek the number two post. Texas Sen. John Cornyn, who heads the Senate Republicans' campaign arm, might also seek to move up in the leadership.
Senate Republicans, however, will be losing a fierce partisan and articulate advocate on a wide range of issues when Kyl steps down. Kyl joins other departing senators, including Sen. Kay Bailey Hutchison, R-Texas; Sen. Joe Lieberman, I-Connecticut; Sen. Kent Conrad, D-North Dakota; and Sen. Jim Webb, D-Virginia, who announced Wednesday he would not run for re-election.
In recent years Kyl has been at the center of debates on everything ranging from the interrogation of terror suspects to immigration and, most recently, the nuclear arms reduction treaty with Russia.
He is known as a tough negotiator. Democrats have told CNN in the past they respect but also fear him at the negotiating table.
Kyl has also been a leading voice from his perch on the Senate Judiciary Committee, especially when it came to questioning President Barack Obama's Supreme Court nominees.
Kyl's announcement set off speculation about who might run to replace him. A source close to Rep. Jeff Flake, R-Arizona, said the congressman would make a decision in the next few days.
There is "very strong likelihood" he will run, the source said.
At the news conference, Kyl said he essentially made up his mind not to seek another term after he was re-elected in 2006. But he did not make a final decision until recently.
"I think it's better to leave when, in effect, people have a fairly good attitude about you than having to be hounded out of office like, unfortunately, some of my colleagues have been experiencing," he said.