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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-γ (IFN-γ) is a key pro-inflammatory mediator that is expressed at high levels in atherosclerotic lesions. IFN-γ regulates the function and properties of all the cell types in the vessel wall. The precise role of IFN-γ 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-γ signaling.