High dietary fat intake is a major risk factor for the development of obesity, which is frequently associated with diseases such as hypertension and diabetes and thus accelerated atherosclerosis. Angiotensin II and endothelin-1 are powerful growth factors and vasoconstrictors implicated in regulating vascular tone, vascular structure, and inflammation. Reduced bioactivity of nitric oxide and increased formation of reactive oxygen species (ROS) have been associated with obesity and high dietary fat intake. This article reviews the effects of high-fat diet on vascular functional changes in rodents and humans. Changes include alterations in vasoconstrictor function and receptor expression, and modulators of endothelium-dependent vascular tone (eg, nitric oxide- or endothelium-dependent contracting factor-mediated responses). Novel vasodilator effects of ROS and the anatomic heterogeneity of vascular responses are discussed. The beneficial effects of vasoactive mediators on vascular function could play a role for susceptibility to obesity-dependent hypertension, which is present in many, but not all, obese patients.