Interferon gamma (IFN-gamma), a pleotropic cytokine, has been shown to be important to the function of virtually all immune cells and both innate and adaptive immune responses. In 1986, early clinical trials of this cytokine began to evaluate its therapeutic potential. The initial studies focused on the tolerability and pharmacology of IFN-gamma and systematically determined its antitumor and anti-infection activities. In the 20-plus years since those first trials, IFN-gamma has been used in a wide variety of clinical indications, which are reviewed in this article.