The most significant target zone Friday will be from South Dakota down through West Texas.
Up to 50 million people could be affected based on areas at risk for severe weather, according to the National Weather Service Storm Prediction Center.
The system is expected to gain strength Saturday as the storm shifts slightly east, with the most significant threat from the Plains to the Gulf Coast.
It will likely hit populated cities such as Dallas, Houston and Oklahoma City. Hail could exceed the size of a tennis ball or even a baseball.
On Sunday, the storm likely will continue east, targeting Midwest states such as Illinois, Indiana and Michigan.
On the heels of this system, yet another potential significant storm event will appear early next week for portions of the southern Plains and Mississippi Valley.