During the early weeks of human gestation, hematopoietic cells first emerge within the extraembryonic yolk sac (primitive hematopoiesis) and secondarily within the truncal arteries of the embryo. This second wave includes the stem cells giving rise to adult-type lymphohematopoiesis. In both yolk sac blood islands and embryonic aorta, hematopoietic cells arise in the immediate vicinity of vascular endothelial cells. In vitro hematopoietic differentiation of endothelial cells stringently sorted from human embryonic and fetal blood-forming tissues has demonstrated that primitive endothelium lies at the origin of incipient hematopoiesis. These anatomically and temporally localized blood-forming endothelial cells are ultimately derived from a rare subset of mesodermal angio-hematopoietic stem cells, or hemangioblasts. The evidence for an early progenitor of blood-forming cells within the walls of human embryonic blood vessels concurs with parallel data obtained from lower vertebrate, avian, and murine models. Importantly, converging results have recently been obtained with in vitro differentiated human embryonic stem cells, in which we have modeled primitive and definitive hematopoiesis via an endothelium-like developmental intermediate.