Recent insights into the pathogenesis of vascular disease have opened up a new frontier that has implications for future therapies. The vasculature has been redefined as a vital organ that can regulate its own tone and structure via numerous cellular mechanisms. The endothelium plays the role of gatekeeper in this process, sensing and responding to stimuli and activating various vasoactive systems that function as mediators. Locally generated vasoactive substances such as angiotensin II and nitric oxide appear to be important determinants of vessel function and structure. Vasoactive substances generated within the endothelium influence cell proliferation and cell death in a complex interplay that, when disturbed, can result in structural alteration known as vascular remodeling. Normal vascular homeostasis is maintained by a balance between vasoconstrictors such as angiotensin II and vasodilators such as nitric oxide. Endothelial dysfunction involves an imbalance between vasoactive substances such that perturbations in the regulation of tone, hemostasis, and vessel structure result in the development of cardiovascular diseases, such as hypertension, atherosclerosis, and heart failure.