GATA-2 is an essential transcription factor that regulates multiple aspects of hematopoiesis. Dysregulation of GATA-2 is a hallmark of acute megakaryoblastic leukemia in children with Down syndrome, a malignancy that is defined by the combination of trisomy 21 and a GATA1 mutation. Here, we show that GATA-2 is required for normal megakaryocyte development as well as aberrant megakaryopoiesis in Gata1 mutant cells. Furthermore, we demonstrate that GATA-2 indirectly controls cell cycle progression in GATA-1-deficient megakaryocytes. Genome-wide microarray analysis and chromatin immunoprecipitation studies revealed that GATA-2 regulates a wide set of genes, including cell cycle regulators and megakaryocyte-specific genes. Surprisingly, GATA-2 also negatively regulates the expression of crucial myeloid transcription factors, such as Sfpi1 and Cebpa. In the absence of GATA-1, GATA-2 prevents induction of a latent myeloid gene expression program. Thus, GATA-2 contributes to cell cycle progression and the maintenance of megakaryocyte identity of GATA-1-deficient cells, including GATA-1s-expressing fetal megakaryocyte progenitors. Moreover, our data reveal that overexpression of GATA-2 facilitates aberrant megakaryopoiesis.