Tissue regeneration and several diseases such as tumor and atherosclerosis depend on new vessel formation by both angiogenesis and vasculogenesis. Endothelial cells (ECs) are widely considered to be the active cellular component in these processes, followed by contractile cells such as pericytes and smooth muscle cells. The best known sources providing these cell types or their progenitors are ECs lining the vessel lumen and bone marrow. As easily evident, the vessel wall was recognized as being a passive player to a great extent except ECs of the vascular intima. Particularly, the vascular adventitia has been considered as a passive layer rather than an active part of the vessel wall. But results provided during the last few years have led to a revision of this classical view because of an apparent stem cell niche function of the vascular adventitia. This review aims to sum up findings identifying the vessel wall as an important stem cell reservoir and discusses its impact on health and disease.