Atherosclerosis is an inflammatory disease. This article reviews the emergence of this concept from studies of patients and their lesions, experimental animal models, and epidemiological cohorts. Immunohistochemical studies identified immune cells and mediators and provided evidence for inflammatory activation in the atherosclerotic lesion. In parallel, cell culture studies demonstrated the capacity of vascular cells to interact with immune cells. Subsequent studies of clinical and epidemiological materials have identified inflammatory markers and immunoregulatory genes as contributors of risk for myocardial infarction and stroke. Finally, experiments using gene-targeted mice have provided mechanistic understanding of the disease process. It is now thought that the atherosclerotic process is initiated when low-density lipoproteins accumulate in the intima, activate the endothelium, and promote recruitment of monocytes and T cells. Monocytes differentiate into macrophages, internalize modified lipoproteins, and end up as foam cells. T cells in lesions recognize local antigens and mount T helper-1 responses that contribute to local inflammation and plaque growth. This atherogenic pathway is counterbalanced by anti-inflammatory signals provided by regulatory immunity. Intensified inflammatory activation may lead to local proteolysis, plaque rupture, thrombus formation, ischemia and infarction. Novel therapeutic opportunities may emerge from understanding the role of inflammation in atherosclerosis.