Quantitative studies of retinal vascular caliber using new computer-assisted retinal imaging systems have allowed physicians and researchers to understand the influence of systemic, environmental, and genetic factors on retinal vascular caliber. Retinal vascular caliber changes reflect cumulative response to aging, cardiovascular risk factors, inflammation, nitric oxide-dependent endothelial dysfunction, and other processes. Recent epidemiological studies have shown that changes in retinal arteriolar and venular caliber size may reflect the differential effects of a range of systemic, environmental, and genetic risk factors. Narrower retinal arteriolar caliber and smaller arteriovenous ratio are associated with older age; higher levels of past, current, and future blood pressure and obesity; and predict the incidence of diabetes and coronary heart disease. Wider retinal venular caliber, in contrast, is associated with younger age; impaired fasting glucose and diabetes; dyslipidemia; obesity; systemic marker of inflammation, endothelial dysfunction, and cigarette smoking; and predicts the risk of stroke and coronary heart disease. New data from family and twin studies indicate a significant genetic contribution to retinal vascular caliber, an area that is under investigation. Elucidating the complete range of systemic, environmental, and genetic factors linked with retinal vascular caliber changes may provide critical insight into the etiology, pathogenesis, and natural history of early vascular disease not only in the eye but elsewhere in the body.