Infectious diseases continue to claim many lives. Prevention of morbidity and mortality from these diseases would benefit not just from new medicines and vaccines but also from a better understanding of what constitutes protective immunity. Among the major immune signals that mobilize host defense against infection is interferon- γ (IFN- γ ), a protein secreted by lymphocytes. Forty years ago, IFN- γ was identified as a macrophage-activating factor, and, in recent years, there has been a resurgent interest in IFN- γ biology and its role in human defense. Here we assess the current understanding of IFN- γ , revisit its designation as an “interferon,” and weigh its prospects as a therapeutic against globally pervasive microbial pathogens.