In the late 1980s, several research groups independently discovered the founding member of the GATA family of transcription factors, GATA-1. Each group had evidence that GATA-1 played an important role in erythroid gene expression, but little did they know that it would turn out to be a key regulator of development of not only red blood cells, but of several other hematopoietic cell types as well. Furthermore, few would have guessed that missense mutations in GATA1 would cause inherited blood disorders, while acquired mutations would be found associated with essentially all cases of acute megakaryoblastic leukemia (AMKL) in children with Down syndrome (DS). With respect to the latter disorder, the presence of a GATA1 mutation is now arguably the defining feature of this leukemia. In this review, I will summarize our current knowledge of the role of GATA-1 in normal development, and discuss how mutations in GATA1 lead to abnormal and malignant hematopoiesis.