GATA-1 exerts a concentration-dependent control on the differentiation of erythroid, megakaryocytic, mast, and eosinophilic cells. The concentration of GATA-1 is, in turn, regulated by specific sequences within the GATA-1 locus. On the basis of its levels of expression, the GATA-1 protein becomes associated with suitable partners forming transcription complexes that, by binding to lineage-specific enhancers, activate the expression of the corresponding target genes. Instrumental to our understanding of the role of GATA-1 in hemopoietic differentiation has been the generation of genetically engineered mutant mice and the discovery of naturally occurring mutations associated with either inherited or acquired human pathologies. We review our current understanding of the role of GATA-1 in normal and neoplastic hematopoiesis as emerging from these genetic approaches.