The cytokine interferon-gamma (IFN-γ) is the only known member of the type II family of interferons, and as such, binds to its own distinct receptor. It is important in host defense against infection, as well as adaptive immune responses. While a wide array of cytokines are known to be involved in adverse remodeling of the heart and the progression to heart failure, the role of IFN-γ is unclear. Recent evidence from clinical studies, animal models of myocarditis and hypertension, as well as isolated cell studies, provide conflicting data as to whether IFN-γ is pathological or protective in the heart. Thus, it is important to highlight these discrepant findings so that areas of future investigation can be identified to more clearly determine the precise role of IFN-γ in the heart. Accordingly, this review will (1) discuss the source of IFN-γ in the diseased heart; (2) summarize the data from animal studies; (3) discuss the effects of IFN-γ on isolated cardiac fibroblasts and cardiomyocytes; (4) identify signaling mechanisms that may be invoked by IFN-γ in the heart; and (5) present the clinical evidence supporting a role for IFN-γ in heart failure.