Considerable effort has been made in recent years in defining the embryonic origin of the hematopoietic stem cell (HSC). Using transgenic mouse models, a number of genes that regulate the formation, self-renewal, or differentiation of HSCs have been identified. Of particular interest, it has recently been shown that key regulators of definitive blood formation played a crucial role in adult HSC development. Specifically, the use of some of these regulatory molecules has dramatically improved the potential of adult HSC expansion. Furthermore, the elucidation of the molecular phenotype of the HSC has just begun. Finally, unexpected degrees of HSC developmental or differentiation plasticity have emerged. In this review, we will summarize the recent advances made in the human HSC field, and we will examine the impacts these discoveries may have clinically and on our understanding of the organization of the human hematopoietic system.