In a statement, Flake praised Kyl's career in public service, calling Kyl "a tireless advocate" and a personal friend. "His retirement will create a huge void," Flake said. Flake did not mention his own potential candidacy.
But he won't be alone. Reps. Trent Franks, Dave Schweikert and Ben Quayle could all contemplate their own campaigns, and there is no shortage of Republican state legislators who have their eyes on higher office. Ex-Reps. John Shadegg and J.D. Hayworth are both expected to explore the race as well.
"It's probably going to be a pretty strong year fro Republicans. We have a very strong bench," Kyl said. He said he would not endorse any candidate in the GOP field "at least for a while. Maybe at some future point I will."
Democratic Rep. Gabrielle Giffords, recovering from an assassination attempt earlier this year, has long been seen as the party's best hope to win a statewide campaign. But Giffords' injuries remain severe, despite a seemingly rapid recovery, and she may not be able to run. Democrats could also turn to Homeland Security Secretary Janet Napolitano, though it's unclear whether the former Arizona governor would leave the administration to return to her state.
Other Democrats mentioned for the position include U.S. Attorney Dennis Burke and ex-Rep. Ann Kirkpatrick, who lost her seat in 2010.
Beth Reinhard and Ben Terris contributed to this report.
This story was updated at 1:26 p.m.