The film is inspired by the "Crazy Eights" unmanned train incident in 2001. The train, led by CSX Transportation SD40-2 #8888, left its Walbridge, Ohio rail yard and began a 66-mile journey through northwest Ohio with no one at the controls, after the engineer got out of the originally slow-moving train to correctly line a switch, mistakenly believing he had properly set the train's dynamic braking system, just as his counterpart in the movie did. Two of the real train's tank cars also contained thousands of gallons of molten phenol, similar to the fictional train in the film.
Rosario Dawson is a real-life train aficionado. She travels on trains all over the world, wherever possible.
Chris Pine performed all of his own stunts. Denzel Washington had seven stuntmen, one for each day of live shots on running trains. According to Tony Scott, in addition to insurance concerns, "D's got a fear of heights, and I had him up at 25 feet on a 50 mph train, which was no easy task." When Washington is on top of a tanker car, that's really him, not CGI.
According to the extras on the DVD, the runaway train was actually being run by a remote control, similar to a toy radio-controlled car.