Unlike all other oxidases, microsomal flavin-containing monooxygenases (FMO) discriminate between essential and foreign compounds by excluding the former rather than selectively binding the latter. As Daniel Ziegler describes here, xenobiotics that readily cross cell membranes can enter the catalytic cavity, whereas charged groups on essential metabolites that prevent their passive diffusion out of the cell also block their access to FMO. FMO appears to be ideally adapted to catalyse the detoxification of structurally diverse soft nucleophiles (e.g. alkaloids with basic side-chains and organic sulfur xenobiotics) so abundant in food derived from plants.