Blood formation (hematopoiesis) entails the generation of hematopoietic stem cells (HSCs) within the embryo and subsequent commitment of multipotential progenitors to differentiation along single lineages. These processes are controlled in large part by cell-restricted transcription factors which cooperate with more widely expressed factors to direct lineage-specific gene expression. Candidate hematopoietic transcriptional regulators have been identified by characterizing factors mediating cell-specific gene transcription and by defining genes involved in chromosomal rearrangements in leukemia. The application of transgenic and embryonic stem cell methods have provided insights into their in vivo functions and suggested mechanisms by which lineage selection may be achieved. One of the first, and best, characterized hematopoietic transcription factors is GATA-1. Herein studies of GATA-1 are reviewed to illustrate how manipulations of its locus in the mouse have contributed to current understanding in unique and unexpected ways.