Prospective isolation of hematopoietic stem and progenitor cells has identified the lineal relationships among all blood-cell types and has allowed their developmental mechanisms to be assayed at the single-cell level. These isolated cell populations are used to elucidate the molecular mechanism of lineage fate decision and of its plasticity directly by stage-specific enforcement or repression of lineage-instructive signaling in purified cells. With an emphasis on the myeloid lineage, this review summarizes current concepts and controversies regarding adult murine hematopoietic development and discusses the potential mechanisms, operated by single or by multiple transcription factors, of myeloid lineage fate decision.