Endothelial cell function in all segments (arterioles, capillaries, and venules) of the microvasculature is compromised in tissues exposed to ischemia and reperfusion (I/R). This endothelial cell dysfunction is manifested as an impaired ability of arterioles to vasodilate, enhanced fluid filtration and leukocyte plugging in capillaries, and leukocyte‐endothelial cell adhesion and increased protein extravasation in venules. An imbalance in the production of reactive oxygen species and nitric oxide contributes to most of these responses. The risk factors for cardiovascular disease, hypercholesterolemia, diabetes, and hypertension all appear to exacerbate the microvascular responses to I/R. A common feature of the deleterious effects of these risk factors is the enhanced oxidant stress experienced by endothelial cells, which appears to promote leukocyte‐endothelial cell adhesion via transcription‐independent (early response) and dependent (late response) processes. The exaggerated endothelial barrier dysfunction elicited by I/R in hypercholesterolemic animals is linked to the enhanced leukocyte recruitment, while the enhanced protein extravasation in postischemic venules of diabetic animals occurs independently of leukocyte recruitment.