Human CB was collected and exposed for 7 days to a cytokine cocktail or a cytokine cocktail plus HDACI in the presence (A) or absence (B) of serum. CB cells cultured in the presence of cytokines and HDACI exhibited increased numbers of cells expressing HSC phenotypes, including increased production of ALDH, upregulation of HSC surface markers CD90, c-Kit, integrin α6, and CXCR4, and expression of the pluripotent genes OCT4, SOX2, and NANOG (B). Surprisingly, the presence of serum decreased the efficiency of HDACI-associated HSC expansion (A). Cells expanded in in the presence of cytokines and HDACI had a much greater capacity to repopulate hematopoietic cell populations and engraft following transplantation into severely immune-deficient animals (B). The study by Chaurasia et al. (4) raises several questions for future consideration: What serum factors block full HSC expansion? What other intracellular factors are involved in epigenetic reprogramming of HSCs? Will other chromatin-remodeling agents and/or small-molecule inducers of pluripotency promote ex vivo expansion of human HSCs alone or in combination with HDACIs? Can expanded HSCs with increased pluripotent gene expression be used for more efficient generation of fully programmed iPSCs?