The transcription factor GATA‐1 and its cofactor FOG‐1 are essential for the normal development of erythroid cells and megakaryocytes. FOG‐1 can stimulate or inhibit GATA‐1 activity depending on cell and promoter context. How the GATA‐1–FOG‐1 complex controls the expression of distinct sets of gene in megakaryocytes and erythroid cells is not understood. Here, we examine the molecular basis for the megakaryocyte‐restricted activation of the αIIb gene. FOG‐1 stimulates GATA‐1‐dependent αIIb gene expression in a manner that requires their direct physical interaction. Transcriptional output by the GATA‐1–FOG‐1 complex is determined by the hematopoietic Ets protein Fli‐1 that binds to an adjacent Ets element. Chromatin immunoprecipitation experiments show that GATA‐1, FOG‐1 and Fli‐1 co‐occupy the αIIb promoter in vivo. Expression of several additional megakaryocyte‐specific genes that bear tandem GATA and Ets elements in their promoters also depends on the physical interaction between GATA‐1 and FOG‐1. Our studies define a molecular context for transcriptional activation by GATA‐1 and FOG‐1, and may explain the occurrence of tandem GATA and Ets elements in the promoters of numerous megakaryocyte‐expressed genes.