Dr. Lightman, his co-workers, and his company are all based on the real-life Dr. Paul Ekman and the Ekman Group.
Most of the actors went on a micro-expressions course before they started filming the show - for preparation. Except for Tim Roth, who avoided learning most of the actual science because he didn't want it affecting his relationships with his family and friends. He'd seen what it can do from the show.
Kay Panabaker played Emily Lightman for the pilot episode. Her one scene was opposite Tim Roth begging him not to use "covert science" on her date for the evening. After filming she was recast with Hayley McFarland. The scene was re-shot and the aired version featured McFarland. A picture of Panabaker can still be seen of Cal's desk though. Best Buy gave customers a free DVD in early 2009 with the "Lie To Me" pilot on it. This version featured Kay Panabaker in the role of Emily.
Cal Lightman was American in the original script, and Tim Roth auditioned with an American accent. It was only after he had been cast that series creator Samuel Baum decided to make the character British, so that Roth could make the part his own.
Tim Roth's and Jennifer Beal's second collaboration, the first being Four Rooms (1995).
On a Spring 2017, season 2 of Match Game, host Alec Baldwin did his usual segment where he introduced all the celebrity talent and inquired silly questions from them. Mekhi Phifer was a guest and when asked by Alec, after being introduced as the star of the show Lie to Me, what would be an example of him lying, Mekhi wittingly retorted that it would be a lie for him to say that he enjoyed working on that show.