Hematopoietic development and homeostasis are based on hematopoietic stem cells (HSCs), a pool of ancestor cells characterized by the unique combination of self-renewal and multilineage potential. These two opposing forces are finely orchestrated by several regulatory mechanisms, comprising both extrinsic and intrinsic factors. Over the past decades, several studies have contributed to dissect the key role of niche factors, signaling transduction pathways, and transcription factors in HSC development and maintenance. Accumulating evidence, however, suggests that a higher level of intrinsic regulation exists; epigenetic marks, by controlling chromatin accessibility, directly shape HSC developmental cascades, including their emergence during embryonic development, maintenance of self-renewal, lineage commitment, and aging. In addition, aberrant epigenetic marks have been found in several hematological malignancies, consistent with clinical findings that mutations targeting epigenetic regulators promote leukemogenesis. In this review, we will focus on both normal and malignant hematopoiesis, covering recent findings that illuminate the epigenetic life of HSCs.