Blood cell formation is a highly regulated process that relies on the ability of a limited number of hematopoietic stem cells to undergo self-renewal or commitment into lineage-restricted progenitors. The daily maintenance of circulating blood cells and the adaptation to abnormal circumstances that alter the tissue homeostasis is ensured by the expansion and the differentiation of committed progenitors. Neoplastic transformation of hematopoietic cells is an extreme manifestation of the inability to coordinate proliferation and differentiation in the progenitor cell pool. Hematopoiesis-specific transcription factors play a central role in these processes both as normal regulators or, when aberrantly activated, as the pathogenetic agents in disease initiation and progression.