An elite team of FBI profilers analyze the country's most twisted criminal minds, anticipating their next moves before they strike again. The Behavioral Analysis Unit's most experienced agent is David Rossi, a founding member of the BAU who returns to help the team solve new cases.

Raymond "Red" Reddington, one of the FBI's most wanted fugitives, surrenders in person at FBI Headquarters in Washington, D.C. He claims that he and the FBI have the same interests: bringing down dangerous criminals and terrorists. In the last two decades, he's made a list of criminals and terrorists that matter the most but the FBI cannot find because it does not know they exist. Reddington calls this "The Blacklist". Reddington will co-operate, but insists that he will speak only to Elizabeth Keen, a rookie FBI profiler.

Murder in the First follows homicide detectives Terry English and Hildy Mulligan as they investigate a multitude of tragedies in San Francisco.