Runx1 binds DNA in cooperation with CBFβ to activate or repress transcription, dependent upon cellular context and interaction with a variety of co‐activators and co‐repressors. Runx1 is required for emergence of adult hematopoietic stem cells (HSC) during embryonic development and for lymphoid, myeloid, and megakaryocyte lineage maturation from HSC in adult marrow. Runx1 levels vary during the cell cycle, and Runx1 regulates G1 to S cell cycle progression. Both Cdk and ERK phosphorylate Runx1 to influence its interaction with co‐repressors, and the Wnt effector LEF‐1/TCF also modulates Runx1 activities. These links likely allow cytokines and signals from adjacent cells to influence HSC proliferation versus quiescence and the rate of progenitor expansion, in response to developmental or environmental demands. J. Cell. Physiol. 219: 520–524, 2009. © 2009 Wiley‐Liss, Inc.