Democratic Senator Ben Nelson to retire
Democratic Senator Ben Nelson will not seek re-election next year - in a blow to efforts by President Barack Obama's party to keep control of the chamber.
Sen Nelson, 70, was facing a tough campaign for a third term in the Republican-leaning Mid-west state of Nebraska in November 2012.
Republicans viewed the conservative Democrat as vulnerable because of his vote for Mr Obama's health reform.
A net gain of four seats would give Republicans control of the Senate.
Sen Nelson said in a web video on Tuesday: "While I relish the opportunity to undertake the work that lies ahead, I also feel it's time for me to step away from elective office, spend more time with my family and look for new ways to serve our state and nation.
"Therefore, I am announcing today that I will not seek re-election. Simply put, it is time to move on."
Scramble for replacement
Although Sen Nelson's conservative voting record has irked liberals in his party over the years, he supported the president's healthcare reforms - and his ratings suffered as a result.
The departure will cause a political headache for the Democratic party, which has spent more than $1m in an effort to shore up his profile. They must now scramble to find a replacement candidate.
Former Senator Bob Kerrey has been mentioned as a potential substitute, although he has not said whether he would enter the race.
The Republican field is led by state Attorney General Jon Bruning.
Democrats currently hold 51 Senate seats, while Republicans control 47, and there are two independents.
While 23 Democratic-held seats are up for grabs next year, Republicans have to defend only 10.
Democratic incumbents in Ohio, Missouri, Florida and Pennsylvania are also seen as vulnerable.