IFN-? plays key roles in both the innate and adaptive immune response. IFN-? activates the cytotoxic activity of innate immune cells, such as macrophages and NK cells. IFN-? production by NK cells and antigen presenting cells (APCs) promotes cell-mediated adaptive immunity by inducing IFN-? production by T lymphocytes, increasing class I and class II MHC expression, and enhancing peptide antigen presentation. The anti-viral activity of IFN-? is due to its induction of PKR and other regulatory proteins. Binding of IFN-? to the IFNGR1/IFNGR2 complex promotes dimerization of the receptor complexes to form the (IFNGR1/IFNGR2)2 -IFN-? dimer. Binding induces a conformational change in receptor intracellular domains and signaling involves Jak1, Jak2, and Stat1. The critical role of IFN-? in amplification of immune surveillance and function is supported by increased susceptibility to pathogen infection by IFN-? or IFNGR knockout mice and in humans with inactivating mutations in IFNGR1 or IFNGR2. IFN-? also appears to have a role in atherosclerosis.