Understanding the intrinsic pathways that regulate hematopoietic stem cell (HSC) proliferation and self-renewal responses to external signals offers a rational approach to developing improved strategies for HSC expansion for therapeutic applications. Such studies are also likely to reveal new targets for the treatment of human myeloid malignancies because perturbations of the biological processes that control normal HSC self-renewal divisions are believed to drive the propagation of many of these diseases. Here, we review recent findings that point to the importance of using stringent functional criteria to define HSCs as cells with longterm repopulating activity and evidence that activation of the KIT receptor and many downstream effectors serve as major regulators of changing HSC proliferative and self-renewal behavior during development.