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The Runt domain transcription factor PEBP2/CBF is a heterodimer of α and β subunits. Of the three mammalian α subunit genes, which are homologues of the Drosophila gene runt, PEBP2αA/CBFA1 and PEBP2αB/AML1 are critical regulators of osteogenesis and haematopoiesis, respectively. A unique functional interaction between PEBP2αB/AML1 and Ets-1 was recently observed, and provides a clear example of context-dependent transcriptional regulation. An elaborate mechanism of cooperation between the two factors may represent a basis for tissue-specific gene expression, which is thought to be achieved by combinations of specific sets of transcription factors unique to each cell lineage or stage of differentiation. A possible molecular basis for the critical role(s) played by PEBP2/CBF in tissue determination is discussed in light of these observations.