The ability of cytochrome P450 monooxygenases to catalyse a wide variety of synthetically challenging C-H activation reactions makes them highly desirable biocatalysts both for the synthesis of chiral intermediates and for late stage functionalisations. However, P450s are plagued by issues associated with poor expression, solubility and stability. Catalytically self-sufficient P450s, in which the haem and reductase domains are fused in a single protein, obviate the need for additional redox partners and are attractive as biocatalysts. Here we present a panel of natural self-sufficient P450s from thermophilic organisms (CYP116B65 from A. thermoflava, CYP116B64 from A. xiamenense, CYP116B63 from J. thermophila, CYP116B29 from T. bispora and CYP116B46 from T. thermophilus). These P450s display enhanced expression and stability over their mesophilic homologues. Activity profiling of these enzymes revealed that each P450 displayed a different fingerprint in terms of substrate range and reactivity covering reactions as diverse as hydroxylation, demethylation, epoxidation and sulphoxidation. The productivity of the biotransformation of diclofenac to produce the 5-hydroxy metabolite rose by 42-fold using the thermostable P450-AX (> 0.5 g L-1 h-1) compared to the previously reported P450-RhF system. In conclusion, we have generated a toolkit of thermostable self-sufficient P450 biocatalysts, with broad substrate range and reactivity.