The part of Malcolm was originally written to be nine years old, so Frankie Muniz, being 13 at the time, thought he was too old. He even gave his mother a thumbs-down as soon as he came out of the audition room. The producers decided to make Malcolm around 12, and give Muniz the part. When the young actor found out he got it, he jumped on the hotel bed.
Bryan Cranston did several of his own stunts. Besides the cartwheel and the headstand, he did his own roller disco skating, spending all the free time he had in the 1-1/2 weeks he had to learn how to skate. After one of the show's writers asked jokingly whether Cranston would be willing to wear a suit of live bees, he said he would, so they wrote a script around the idea (The Bots and the Bees (2000)). He ended up covered in 10,000 bees, and only got stung once.
Aaron Paul auditioned for the role of Francis. He would later be cast in Breaking Bad (2008), which also starred Bryan Cranston (Hal).
"Krelboyne", the name of the class of gifted students to which Malcolm belongs, is taken from the name of the nerdy hero of The Little Shop of Horrors (1960).
Although the family's surname was revealed as Wilkerson in the pilot episode, it was decided afterwards that they should not have a last name. A running joke on-set was that the family's last name was "Nolastname". This is officially confirmed in the final episode, Graduation (2006), when Francis drops his work pass, and his surname is briefly seen. Further confirmation can be seen when Malcolm is introduced to the stage for his speech. His last name is not heard, as the microphone screeches at the crucial moment, but you can read the announcer's lips clearly saying "Malcolm Nolastname".