IFN-gamma is a pleiotropic cytokine endowed with potent immunomodulatory effects whose expression was long considered to be restricted to T and NK cells. Only recently, it became evident that IFN-gamma production can also occur in other cell types, including monocyte/macrophages. However, the biological relevance of macrophage IFN-gamma is still unclear. The purpose of this article is to provide an overview of the collected evidence demonstrating IFN-gamma expression in macrophages and to discuss the possible biological significance of this cytokine production in the early phase of host response to infectious agents.