Transcription factors originally identified as drivers of erythroid differentiation subsequently became linked to megakaryopoiesis, reflecting the shared parentage of red cells and platelets. The divergent development of megakaryocytic and erythroid progenitors relies on signaling pathways that impose lineage‐specific transcriptional programs on non‐lineage‐restricted protein complexes. One such signaling pathway involves RUNX1, a transcription factor upregulated in megakaryocytes and downregulated in erythroid cells. In this pathway, RUNX1 engages the erythro‐megakaryocytic master regulator GATA‐1 in a megakaryocytic transcriptional complex whose activity is highly dependent on the P‐TEFb kinase complex. The implications of this pathway for normal and pathological megakaryopoiesis are discussed. J. Cell. Biochem. 107: 377–382, 2009. © 2009 Wiley‐Liss, Inc.