After moving from London to New York City, Sherlock Holmes (Jonny Lee Miller) works with the NYPD as a consulting detective with an uncanny ability to read people and analyze crime scenes. Joan Watson (Lucy Liu) is Sherlock's sober companion, hired by his father to make sure that the enigmatic detective doesn't relapse into self-destructive drug use. Over the course of the pilot, she realizes that she has a knack for detective work as well.

Sherlock's contact in the police department is Captain Tobias Gregson (Aidan Quinn), who invites him to investigate a home invasion that has led to the disappearance of the woman who lived in the townhouse. While Sherlock is able to find the victim's body and track down the killer, proving his guilt is a far more difficult task.