Six months after the events of last season, Booth, Brennan, daughter Christine and the new baby are ostensibly living a dream life, a world away from the murder-filled life they left behind. But a case with close personal ties to the couple compels Brennan to become involved in the forensic analysis of the remains, and Booth mysteriously goes missing, prompting an FBI investigation into his whereabouts led by Agent Grace Miller (guest star Kim Raver), who works closely with FBI Agent James Aubrey on the case. However, tensions rise when Miller tries to investigate one of the team's own as the primary suspect. The case also brings Brennan into contact with a member of Booth's family (guest star Dilshad Vadsaria), and "squintern" Arastoo Vaziri (guest star Pej Vahdat), who has been filling in as lead forensic anthropologist during Brennan's absence, hopes the temporary position becomes permanent.

On Brennan and Booth's first official day back at their respective positions at the Jeffersonian and the FBI, things get exciting when remains are found at a fish farm under suspicious conditions, prompting them to investigate. After it's discovered that someone harvested several of the victim's internal organs before he was dumped in the water, Angela tracks down the seller and buyer of the organs to try to uncover important details in the case. Meanwhile, Booth readjusts to his position back at the FBI and discovers Aubrey has taken over his old office; Hodgins pushes Angela to showcase her photography work; and Cam struggles with her decision to choose work over her relationship with Arastoo.