Chromatin assembly and remodeling complexes alter histone-DNA interactions by using the energy of ATP hydrolysis catalyzed by nucleosome-dependent ATPase subunits. Several classes of ATP-dependent chromatin remodeling complexes exist, including the ISWI family. ISWI complexes disrupt histone-DNA interactions in vitro by facilitating nucleosome sliding. Snf2h is a widely expressed ISWI ATPase. We investigated the role of the Snf2h gene in mammalian development by generating a null mutation in mice. Snf2h heterozygous mutant mice are born at the expected frequency and appear normal. Snf2h-/- embryos die during the periimplantation stage. Blastocyst outgrowth experiments indicate that loss of Snf2h results in growth arrest and cell death of both the trophectoderm and inner cell mass. To investigate the effect of decreased Snf2h levels in adult cells, we performed antisense inhibition of Snf2h in human hematopoietic progenitors. Reducing Snf2h levels inhibited CD34+ progenitors from undergoing cytokine-induced erythropoiesis in vitro. Our results indicate that Snf2h is required for proliferation of early blastocyst-derived stem cells and adult human hematopoietic progenitors. Cells lacking Snf2h are thus prevented from further embryonic development and differentiation.