He said he "will take a sabbatical from public life" and "return to my professional roots as a healer and to refocus my creative energies on innovative solutions to seemingly insurmountable challenges Americans face."
Frist announced when he first ran for the Senate that he would retire after two terms. His decision not to seek the White House thus caps a 12-year stint in electoral politics in which he rose from an underdog in his 1994 Senate campaign to the position of majority leader a mere eight years later.
Among the Republicans already exploring a White House bid are Sen. John McCain of Arizona, former New York mayor Rudy Giuliani and Massachusetts Gov. Mitt Romney.
Other potential GOP contenders include Sens. Sam Brownback of Kansas and Chuck Hagel of Nebraska, Govs. George Pataki of New York and Mike Huckabee of Arkansas, and Rep. Duncan Hunter of California.
Democrats, like Republicans, have an extensive roster of potential presidential hopefuls. Sens. Hillary Rodham Clinton of New York and Barack Obama of Illinois are the best known nationally; outgoing Iowa Gov. Tom Vilsack will be first to formally declare his candidacy, on Thursday, in his home state. Indiana Sen. Evan Bayh also is weighing a bid.
Former Democratic Gov. Mark Warner of Virginia has announced he will not run for the presidency in 2008. Warner, like Frist, had begun putting in place a campaign organization to raise money and line up supporters in early caucus and primary states, as well as nationally.
Frist, 54, has been under investigation for more than a year by the Securities and Exchange Commission, which is probing allegations of insider trading in connection with the sale of shares in HCA Inc. Frist's father and brother founded the firm and it formed the foundation of the senator's considerable personal wealth. He has vehemently denied any wrongdoing, although resolution of the investigation has eluded him.
Also embarrassing was a disclosure by The Associated Press in August that Frist had not met the continuing medical education requirement needed to remain licensed, although he submitted paperwork to Tennessee officials indicating that he had. He quickly complied with the requirements and retained his license.
Several officials said the SEC investigation was not at the heart of Frist's decision. Rather, they said, he had come to the conclusion that he would have faced a formidable challenge in gaining the nomination, without little assurance of success.
Frist was a physician with no experience in politics when he challenged Democratic Sen. Jim Sasser. He was swept into office in that year's Republican landslide.
In the 2001-02 election cycle Frist headed the Senate campaign committee and the party gained seats. He was chosen majority leader after the election when Sen. Trent Lott, R-Miss., was forced to step down after making racially insensitive remarks at a birthday celebration for Sen. Strom Thurmond, R-S.C.
Frist was widely criticized in 2005 for pandering to religious conservatives by injecting himself into the debate over Terri Schiavo, the brain-damaged Florida woman whose feeding tube was removed. Frist viewed a videotape of the woman, then publicly questioned the diagnosis of her doctors. An autopsy later confirmed their judgment, not his.
Frist's political action committee, which allowed him to travel and build a donor base, had raised $7.5 million between Jan. 1, 2005, and Oct. 18, 2006. The PAC spent $8.2 million during that period.
He had traveled to Iowa and New Hampshire - the states that will pick the first GOP convention delegates - as part of maneuvering toward the starting line in the presidential campaign.