Atherosclerosis is considered to be a form of chronic inflammation governed by a complex network of inter- and intra-cellular signaling pathways. The pleiotropic cytokine interferon-gamma (IFN-gamma) is a key pro-inflammatory mediator that is expressed at high levels in atherosclerotic lesions. IFN-gamma regulates the function and properties of all the cell types in the vessel wall. The precise role of IFN-gamma in atherogenesis is complex, with both pro- and anti-atherogenic actions being identified. This review will discuss these actions of the cytokine along with recent findings that have emerged from mouse models of atherosclerosis that are deficient in IFN-gamma signaling.