After falling from grace in England and spending some time in a rehabilitation facility, the brilliant sleuth Sherlock Holmes (Jonny Lee Miller) moves to New York City. His wealthy father hires Dr. Joan Watson (Lucy Liu), a former surgeon and sober companion, to live with Sherlock and together they work as police consultants for the NYPD. With Sherlock's deducing genius and Watson's medical skills, they help Captain Tommy Gregson and Detective Marcus Bell solve cases, while friends and enemies from the classic works of Sir Arthur Conan Doyle come back to interact with the modern-day Sherlock.
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When a groundbreaking artificial intelligence software program is stolen, Sherlock agrees to take on the case but enlists Joan's assistance in solving it. Meanwhile, Joan confronts Sherlock about his motives when she learns he has contacted her boyfriend.