Solanaceous plants produce sesquiterpenoid phytoalexins to defend themselves against a variety of pathogens. These toxic compounds are not only harmful to the pathogen but also to the plant, and thus need to be detoxified by the plant after the threat has been eliminated. We report that the detoxification of rishitin, the major phytoalexin in potato tubers and tomato fruits, is mediated by a cytochrome P450 CYP76 family enzyme via the hydroxylation of the isopropenyl group resulting in the formation of 13-hydroxyrishitin, also known as rishitin-M1. We further observed hydroxylation of the potato phytoalexins solavetivone, lubimin and oxylubimin by the same enzyme. Constitutive expression of CYP76 in Nicotiana benthamiana also led to a reduction of the non-potato phytoalexins capsidiol and its derivative capsidiol 3-acetate. We therefore annotated this enzyme as sesquiterpenoid phytoalexins hydroxylase, SPH. This broad range of substrates indicates that SPH functions as a general phytoalexin detoxification enzyme in Solanaceae, and is therefore relevant for a better understanding of plant-pathogen interaction in solanaceous plants, which comprise many economically important crops, such as potato, tomato, eggplant and pepper.