The transcription factor GATA-1 is specifically expressed in hematopoietic lineages. Prior gene knockout experiments established an essential role for GATA-1 in red blood cell production, but could not provide direct evidence with respect to a requirement in megakaryopoiesis. We summarize here recent lineage-selective gene targeting in mice that establishes critical functions for GATA-1 in controlling megakaryocyte growth and maturation, and platelet production. GATA-1 megakaryocytes are delayed in their cellular maturation, exhibit marked hyperproliferation and generate fewer than normal, yet enlarged, platelets in vivo. Thus GATA-1 is a central regulator in both the erythroid and megakaryocytic lineages.