Air pollution is a leading global risk factor for cardiovascular disease. Experimental animal models and short-term studies in humans are consistent with systemic effects of particulate matter smaller than 2.5 microns. Exposure to fine as well as ultrafine particles (<0.1 microns) have been shown to be consistently associated with a number of risk factors including hypertension, diabetes, and abnormalities in lipoproteins. The size of particles and the chemical composition are key determinants of propensity for systemic effects. While direct chemical translocation of smaller particles across the alveolar–capillary membrane is possible, oxidative modification of phospholipids in entities such as lipoproteins and other plasma proteins may represent additional mechanisms by which exposure may transduce systemic effects. Studies in susceptible disease models have been particularly informative as exposure to air pollution appears to aggravate a number of risk factors such as hypertension and diabetes. Collectively, these studies seem to suggest that chronic exposure to air pollution may potentiate the risk factors and may represent a convergent pathway through which air pollution may mediate susceptibility to cardiovascular disease. Air pollution exposure also exerts acute effects through mechanisms that include alterations in vascular tone, coagulation abnormalities, and changes in blood pressure. Collectively, these findings argue for the recognition of air pollution as an independent risk factor for the pathogenesis of cardiovascular disease.