Xanthine oxidoreductase is a complex enzyme found in a wide range of organisms. Recent interest in this enzyme stems from its ability to produce reactive oxygen species under a range of conditions. It is found as a homodimer, each unit containing a molybdopterin cofactor, two iron sulfur centers, and FAD. The enzyme can exist in two forms that differ primarily in their oxidizing substrate specificity. The dehydrogenase form preferentially utilizes NAD+ as an electron acceptor but is able to donate electrons to molecular oxygen. Xanthine dehydrogenase from mammalian sources can be converted to an oxidase form that readily donates electrons to molecular oxygen, but does not reduce NAD+. The catalytic mechanism of both forms of the enzyme can be described in terms of a rapid equilibrium model in which reducing equivalents are distributed rapidly between the different redox centers of the enzyme on the basis of their midpoint potentials. The present commentary gives a brief overview of the literature concerning the rapid equilibrium model and the differences between the two enzyme forms. NADH is also discussed in terms of an alternative to xanthine or hypoxanthine as an electron donor.