A clustering of risk factors, including elevated triglycerides, decreased high-density lipoprotein cholesterol, hyperinsulinemia, and hypertension often are observed in patients who are insulin resistant. Insulin resistance has been found to play a critical role in the development of cardiovascular disease, particularly in patients with type 2 diabetes. Patients with insulin resistance have an increase in small, dense low-density lipoprotein (LDL) cholesterol, which is more atherogenic than large, buoyant LDL cholesterol. In the context of insulin resistance, insulin has reduced effects on the phosphatidylinositol 3 kinase (PI3K) pathway, whereas mitogen-activated protein kinase activity is maintained. The result is an exaggeration of the mitogenic actions of insulin leading to vascular smooth muscle proliferation and elevated plasminogen activator inhibitor (PAI)-1. Notably, nitric oxide-mediated vasodilation also is impaired, further contributing to atherogenicity. In addition, hyperinsulinemia further contributes to cardiovascular risk by promoting thrombosis. Patients who are insulin resistant have decreased fibrinolysis, as indicated by increased levels of PAI-1. Studies have shown that enhancing insulin sensitivity with insulin sensitizers, such as thiazolidinediones, may improve insulin resistance and limit the development of adverse cardiovascular consequences.