Human long-term hematopoietic stem cells (LT-HSC) play a central role in meeting both homeostatic (e.g. ≧1011 blood cells daily) and stress-mediated demands due to their three functional hallmarks: self-renewal, multilineage differentiation, and capacity to remain quiescent for long periods of time. Upon cues to exit this dormant state, LT-HSC must respond and adapt their metabolism and nutrient uptake to meet increased bioenergetic demands for cell growth and differentiation. Simultaneously, the events underlying cellular and metabolic activation must also be suppressed within a subset of LT-HSC to enable re-entry into quiescence and ultimately maintain the LT-HSC pool through self-renewal and prevent malignancy. The demand-adapted regulatory circuits of these early steps of hematopoiesis are emerging and include the interplay of transcriptional, epigenetic and metabolic programs. We have identified a particular class of lipids, sphingolipids, that intersects with stemness regulatory programs including inflammatory and proteostatic quality control pathways to regulate cell fate in human HSCs, and this differs in leukemia stem cells from patients with acute myeloid leukemia (AML). Lipids are emerging as regulators of normal adult stem cell fate in various tissues and in disease. Teasing out how lipids interact with stemness regulatory systems have great promise to yield strategies for improving HSC transplantation and targeting AML.