Incumbent senator Claire McCaskill was unopposed in the Democratic primary and U.S. representative Todd Akin won the Republican nomination with a plurality in a close three-way race.

Years prior, many forecasters considered Claire McCaskill to be the most vulnerable Democratic senator seeking re-election in 2012 due to the state's rightward shift.

This election received considerable media coverage due to controversial comments made by the eventual Republican nominee, Todd Akin, most notably his claim that women could not get pregnant from rape.

[4] Democrats believed that Todd Akin would be the weakest among the likely challengers for the Senate seat, and ads attacking him as "too conservative" were largely viewed as a veiled support for his nomination.

[5][6][7] In McCaskill's memoir, she revealed that she also influenced the Akin campaign by providing polling information, which some election law experts later felt would be a violation of regulations against coordination.

In an interview aired on St. Louis television station KTVI-TV, Akin was asked his views on whether women who became pregnant due to rape should have the option of abortion.

[43] While some voices such as Iowa congressman Steve King supported Akin,[44] senior figures in both parties condemned his remarks and called for him to resign.

Both McCaskill and incumbent governor Jay Nixon, running at the same time, were able to get a large number of votes from rural parts of the state, something President Barack Obama was not able to do.

McCaskill and Nixon were declared the winners of their respective races even before results from the known big Democratic strongholds of St. Louis and Kansas City came in.