The regenerative capacity of hematopoietic stem cells (HSCs) is limited by the accumulation of DNA damage. Conditional mutagenesis of the histone 3 lysine 4 (H3K4) methyltransferase, Setd1a, revealed that it is required for the expression of DNA damage recognition and repair pathways in HSCs. Specific deletion of Setd1a in adult long-term (LT)-HSCs is compatible with adult life and has little effect on the maintenance of phenotypic LT-HSCs in the bone marrow. However, SETD1A-deficient LT-HSCs lose their transcriptional cellular identity accompanied by loss of their proliferative capacity and stem cell function under replicative stress in situ and after transplantation. In response to inflammatory stimulation in vivo SETD1A protects HSCs and progenitors from activation-induced attrition. The comprehensive regulation of DNA damage responses by SETD1A in HSCs is clearly distinct from the key roles played by other epigenetic regulators including the major leukemogenic H3K4 methyltransferase, MLL1, or MLL5, indicating that HSC identity and function is supported by co-operative specificities within an epigenetic framework.