Studies on the multifunctional nature of the transforming growth factor- β (TGF-β) family of cytokines and the enzyme nitric oxide synthase (NOS) have suggested that they mediate a wide variety of vital processes in evolutionarily divergent organisms. Numerous mechanistic studies have investigated the consequences of the regulation of NO by the TGF-β's for mammalian physiology. Studies with several cell types in vitro indicate that TGF-β1 negatively controls the expression of the enzyme responsible for the prolonged production of large amounts NO, the inducible nitric oxide synthase (NOS2; iNOS), by reducing the expression and activity of NOS2 at multiple levels. Recent studies with TGF-β1 null mice or mice which overexpress TGF- β1 suggest that this cytokine may be a primary negative regulator of NOS2 in vivo. The interaction between NOS2 and TGF-β1 may represent a central homeostatic mechanism in mammalian physiology with implications for a variety of human diseases.