The Sign of the Four has a complex plot involving service in East India Company, India, the Indian Rebellion of 1857, a stolen treasure, and a secret pact among four convicts ("the Four" of the title) and two corrupt prison guards. It presents the detective's drug habit and humanizes him in a way that has never been done before.

Sherlock Holmes is famous for his intellectual prowess and is renowned for his skilful use of deductive reasoning, astute observation, and forensic skills to solve difficult cases. Deductive reasoning allows Holmes to impressively reveal a stranger's occupation. Similarly, by studying inanimate objects, he is able to make astonishingly detailed deductions about their owners. This mindset was a major innovation in the field of crime fiction, inspiring authors like Robert J. Sawyer, Neil Gaiman and Stephen King.