Hematopoietic progenitors derived from human embryonic stem cells (hESCs) present both a potential cell source for cell-replacement therapies and an in vitro model for hematopoietic stem cell (HSC) development. Current protocols for the hematopoietic differentiation of hESCs suffer from low efficiency and functional defects in the derived HSCs. Epigenetic mechanisms of HSC development should be addressed to overcome these imperfections. The focus of this review is to summarize the knowledge on the epigenetic regulation of pluripotency and lineage-specific genes with the emphasis on the hematopoietic cell lineage. The potential utilization of this knowledge to improve the generation of HSCs for clinical application is also discussed.