During embryonic development, multilineage HSCs/progenitor cells are derived from specialized endothelial cells, termed hemogenic endothelium, within the yolk sac, placenta, and aorta. Whether hemogenic endothelial cells contribute to blood cell development at other sites of definitive hematopoiesis, such as in the fetal liver and fetal bone marrow, is not known. Also unknown is whether such cells exist within the vasculature of adult bone marrow and generate hematopoietic stem cells after birth. These issues and their clinical relevance are discussed herein.