Cardiovascular disease is associated with damage of the endothelial monolayer leading to endothelial dysfunction and atherosclerosis. A growing body of evidence suggests that circulating endothelial progenitor cells play an important role in endothelial cell regeneration. In this review we discuss the evolving role of stem- and progenitor cells in the maintenance of the vascular wall focusing on new pathophysiological concepts of endothelial cell regeneration. We discuss new insights into vascular stem cell biology derived from experimental and clinical studies.