After losing his wife, Dr. David Styles has dedicated himself entirely to his solitary research in neurobiology, severing most of his ties with the academic world and his friends. In order to perform the experiment that might set the stage for the greatest discovery in the field, he enlists the aid of Samantha Everett, street magician and part-time worker. As his assistant, her first assignment is to find six students in Oxford willing to participate in Dr. Styles' weird experiment. However, as they explore the wonders of the human mind, unexplained events start to occur, and Samantha finds herself entangled in a string of dark secrets and dubious motives weaved by the people around her.

Gray Matter is a traditional point-and-click adventure that marks Jane Jensen's return to the gaming medium. Much like her previous works in the Gabriel Knight series, she doesn't shy away from combining both science and the paranormal in order to create an original story. The player ends up controlling both David and Samantha at different points in the game, which significantly alters the perspective, since they think and tackle situations differently. This can also influence how puzzles are solved in-game.