Jacques Futrelle was most famous for creating the character of Professor S. F. X. Van Dusen, a.k.a. "The Thinking Machine". A gaunt, bony-fingered scholar with an unusually large head and little patience for unscientific explanations, The Thinking Machine could solve seemingly impossible mysteries merely by thinking about them. In the Thinking Machine's most famous case, "The Problem of Cell 13", Professor Van Dusen boasts that, were he arrested and locked in any prison cell, that he could escape within a week using only his ingenuity. "The Problem of Cell 13" was originally published as a serial in the Boston American. Readers were offered prize money for submitting the best solution before the last installment was published. The story is included in most anthologies of famous American mystery/detective stories.

Jacques Futrelle wrote a number of short stories featuring The Thinking Machine, many of which were printed in the popular magazines of the time, such as The Saturday Evening Post. Some of these stories include: The Crystal Gazer; The Scarlet Thread; The Flaming Phantom; The Lost Radium; Kidnapped Baby Blake, a Millionaire. He also published a number of novels, including The Case of the Golden Plate, The Simple Case of Susan, The Diamond Master, Elusive Isabel, The High Hand, Blind Man's Bluff, My Lady's Garter.

Recently, some of the Thinking Machine stories were produced as radio plays in Germany. The series was so popular that the producer, Michael Koser, went on to write over 50 new Thinking Machine mysteries. To date, these have not been translated into English. Jacques and May themselves have now become the main characters in "The Titanic Murders" by historical mystery writer Max Allan Collins. In this fictionalized account, the Futrelles solve two murders that take place on board the Titanic shortly before the disaster.