Democratic incumbents also face tough re-election races in Arkansas, Louisiana, Montana, North Carolina and Alaska — all carried by Republican Mitt Romney in November's presidential election.
Harkin's move opens a rare open Senate seat Iowa. Harkin, Iowa's junior senator, is outranked by Sen. Charles Grassley, who has held the state's other seat since 1980.
Attention will turn to U.S. Rep. Bruce Braley, a fourth-term Democrat from Waterloo who has long been mentioned as a possible Harkin successor. Braley, who was traveling in Iowa, did not immediately return requests by the AP for comments beyond an emailed statement calling Harkin a "mentor" and "progressive force" who leaves "a legacy few will ever match."
Harkin held open the possibility of endorsing a Democrat before the primary if the candidate "is a pragmatic progressive."
Although no Republicans have stepped forward, Harkin's news gives the GOP's private huddles new life.
"There are lots of conversations, but it's very early still," said Nick Ryan, an Iowa Republican campaign fundraiser.
U.S. Rep. Tom Latham of Clive is a seasoned Republican congressman, a veteran House Appropriations Committee member and a robust fundraiser who has won 10 consecutive terms. Aides to Latham declined to comment beyond a statement saying the congressman "respects Sen. Harkin's decision (and) looks forward to continuing to work with him."
Since November, Harkin has stepped up his role as one of the Senate's leading liberal populists.
He was a vocal opponent late last year of Obama's concession to lift the income threshold for higher taxes to avoid the so-called fiscal cliff. Harkin instead supported raising taxes on all earners making more than $250,000 a year.
He also endorsed Obama's call for banning assault rifles and larger ammunition magazines after the Connecticut school shooting.
Despite Harkin's strong political position, he has faced questions about his and his wife's role in developing a namesake policy institute at Iowa State University, Harkin's alma mater. The Harkins and their supporters have been pushing for the institute to house papers highlighting his signature achievements, including the ADA and shaping farm policy as the former chairman of the Agriculture Committee.
Harkin has avoided questions about fundraising for the institute after disclosure reports showed some of its largest donors are firms that have benefited from his policies.
Harkin dismissed that those questions had any bearing on his decision.