PU.1 is a transcription factor that activates gene expression during myeloid and B-lymphoid cell development. It is a key molecule of hematopoiesis. The mutual negative regulation between PU.1 and GATA-1 is detailed within the context of normal and leukemogenic hematopoiesis and the concept of Ôdifferentiation therapyÍ to restore normal cellular differentiation of leukemic cells is discussed.