Cytochromes P450 are nature's efficient nanomachines that catalyze a plethora of reactions in all organisms. These enzymes are phenomenally versatile; they are responsible for detoxifications of foreign compounds (so-called Xenobiotics), and among other processes can perform e.g. sulfoxidation, C-H/C=C activations, carbene-and nitrile-insertion, as well as C-C bond making and cleavage. Such a synthetic versatility makes P450 a favorite model for bio-engineering and evolutionary studies. The paradigmatic catalytic cycle of a P450 starts by the entry of a substrate, which triggers concomitant delivery of two electrons (from a reducing partner) and two protons, finally leading to the formation of the porphyrin-radical-cation oxoiron species, so-called Compound I (Cpd I) which in turn oxidizes the substrate. This mechanistic paradigm has prevailed until the discovery of P450 peroxygenases which utilize hydrogen peroxide to shunt the catalytic cycle, and thereby bypasses the necessity of reducing partner by. The crystal structures of two P450 peroxygenases, P450SPα and P450BSβ, reveal some interesting architectural features, related to substrate-binding. In contrast to P450BM3, which is a bacterial enzyme that catalyzes the hydroxylation of the tails of long-chain fatty acids, in the related peroxygenases P450SPα and P450BSβ, the fatty acids enter the heme site via their carboxylate heads, and undergo hydroxylation, respectively in the or positions (to the carboxylate heads).