Atherosclerosis is a chronic inflammatory disease that is characterized by the development of fibrotic plaques in the arterial wall. The disease exhibits a complex aetiology and its progression is influenced by a number of environmental and genetic risk factors. The cytokine interferon-gamma (IFN-gamma), a key regulator of immune function, is highly expressed in atherosclerotic lesions and has emerged as a significant factor in atherogenesis. Evidence from both mouse models of atherosclerosis and in vitro cell culture has suggested that the role of IFN-gamma is complex since both pro- and anti-atherogenic actions have been affiliated to it. This review will focus on evaluating the contribution of IFN-gamma to atherosclerosis and, in particular, how it regulates immune responses to the disease.