Vascular endothelium regulates cardiovascular function, and endothelial dysfunction is the key initiator for arteriosclerosis and thrombosis and their complications. The endothelium is a dynamic interface that responds to various stimuli and synthesizes and liberates vasoactive molecules such as nitric oxide, prostaglandins, hyperpolarizing factor, and endothelin. Risk factors such as hypertension, hypercholesterolemia, smoking, and hyperglycemia impair the ability of the endothelium to respond to physical or chemical stimulation appropriately, and increased oxidative stress is believed to be a major culprit. This brief article reviews the interplay among several oxidative stress regulators in the vascular wall and highlights therapeutic relevance through deeper understanding of the interplay between the renin-angiotensin system, nicotinamide adenine dinucleotide phosphate, reduced oxidase, bone morphogenic protein 4, and cyclooxygenase 2-derived prostaglandins as a concerted pathogenic cascade in inducing and maintaining endothelial dysfunction in hypertension and diabetes.