In 1964, when three civil-rights workers, two white and one black, mysteriously disappear while driving through Mississippi, two FBI agents, Ward (Dafoe) and Anderson (Hackman), are sent in to investigate. While Ward is young and by-the-book, Anderson is a morally ambiguous seasoned veteran. Together they sift through a variety of leads and come up empty-handed – until the town sheriff's wife (McDormand) steps forward and reveals some surprising information. In order to solve the case, the two contrasting agents must not only overcome the hostility of the local authorities and the black community but contend with their own differences as well.