The Democrats' majority in the upper chamber of Congress has already shrunk from 59 seats to 53, including two independents: Lieberman and Vermont's Bernie Sanders. That means the GOP only needs to win four seats to wrest control of the Senate.
In addition to Conrad, a number of other Democrats could elect to retire from the Senate rather than engage in tough re-election fights . Even if they win, they face the distinct prospect that they will end up serving in the minority.
Sen. Jim Webb, D-Va., faces a challenging re-election battle, while in the Midwest a tricky road lies ahead for Sen. Ben Nelson, D-Neb., who voted in favor of the controversial new health care law.
A slew of other Democratic-held seats, from Sen. Claire McCaskill in Missouri to Sen. Jon Tester in Montana, are currently viewed as toss-ups by political pundits. Other Democrats such as Sen. Sherrod Brown in Ohio and Sen. Joe Manchin in West Virginia are also seen as vulnerable.
While Democrats clearly have much more to lose than Republicans in the upcoming election, some GOP seats are also expected to result in close races. In Nevada, Sen. John Ensign must overcome the poitical fallout from his affair with a former, while in Massachusetts Sen. Scott Brown will seek a second term, a push that seems more likely to end in success now that possible candidates such Sen. Ted Kennedy's widow Vicki have taken themselves out of the running.
All in all, analysts say, the 2012 landscape looks more promising for Republicans than Democrats.
"We've got a long way to go, but the numbers -- with or without retirements -- don't favor Democrats when they have to defend 23 seats," says Jennifer Duffy, a senior editor for the Cook Political Report.