Thermostable enzymes combine catalytic specificity with the toughness required to withstand industrial reaction conditions. Stabilized enzymes also provide robust starting points for evolutionary improvement of other protein properties. We recently created a library4 of at least 2,300 new active chimeras of the biotechnologically important cytochrome P450 enzymes. Here we show that a chimera’s thermostability can be predicted from the additive contributions of its sequence fragments. Based on these predictions, we constructed a family of 44 novel thermostable P450s with half-lives of inactivation at 57°C up to 108 times that of the most stable parent. Although they differ by as many as 99 amino acids from any known P450, the stable sequences are catalytically active. Among the novel functions they exhibit is the ability to produce drug metabolites. This chimeric P450 family provides a unique ensemble for biotechnological applications and for studying sequence-stability-function relationships.