MEIS1 is a transcription factor expressed in hematopoietic stem and progenitor cells (HSPC) and in mature megakaryocytes. In contrast to its role in leukemogenesis, the role of MEIS1 in normal hematopoiesis is largely unknown. We show that MEIS1 can direct human hematopoietic progenitors towards a megakaryocyte-erythroid progenitor (MEP) fate. Ectopoic expression of MEIS1 in CD34+ cells resulted in increased erythroid differentiation at the expense of granulocyte and monocyte (GM) differentiation. MEIS1 overexpression not only skewed differentiation of CMPs towards the erythroid lineage but also reprogrammed GM progenitors towards erythrocyte differentiation. Expression profiling was used to determine the transcriptional changes induced by MEIS1 that lead to the oberved phenotype. A transcriptional program enriched for erythrocytic and megakaryocytic genes was detected. Overall design: Three independent experiments were performed. Total RNA was isolated from lentivirally transduced human CD34+ cells, 48 hours after transduction. Transductions were performed for the two MEIS1 splice variants MEIS1B and MEIS1D. An empty vector was taken along as a control.