Giant cell arteritis (GCA), a vasculitis that targets medium- and large-size arteries, is ranked as a medical emergency because of its potential to cause blindness and stroke. The typical lesions, granulomas in the vessel wall, are formed by IFN-gamma-producing CD4+ T cells and macrophages. CD4+ T cells undergo in situ activation in the adventitia, where they interact with indigenous dendritic cells. Tissue injury is mediated by several distinct sets of macrophages that are committed to diverse effector functions. The dominant tissue injury in the media results from oxidative stress and leads to smooth muscle cell apoptosis and nitration of endothelial cells. Macrophage-derived growth factors are instrumental in driving the response-to-injury program of the artery that causes intimal hyperplasia and vessel occlusion. Clinical manifestations are those of tissue ischemia or a syndrome of exuberant systemic inflammation. The vascular and the systemic components of GCA contribute differentially to the disease, leading to distinct clinical phenotypes of this arteritis. Immunologically most interesting is polymyalgia rheumatica, in which the systemic component is combined with aborted vasculitis, suggesting a role for artery-specific tolerance mechanisms.