Injury to hematopoietic tissues is a major problem limiting the success of cancer therapy, including ionizing radiation, chemotherapy, and immunotherapy. Acute injury to hematopoietic cells challenges hematopoietic stem cells (HSCs) to regenerate for self-renewal and differentiate into different lineages of peripheral blood cells. It is well-documented that HSCs reside in a hypoxia niche and have a lower level of reactive oxygen species (ROS) than their mature progeny. Life-long measurements of local oxygen tension (pO2) in the bone marrow of living mice show that the absolute pO2 of bone marrow is Here, we demonstrate that, in transgenic mice expressing the human manganese superoxide dismutase (MnSOD) gene, a scavenger of ROS in mitochondria, the number and function of hematopoietic stem/progenitor cells (HSPCs) under physiological conditions is enhanced. Importantly, giving MnTnBuOE-2-PyP5+ (MnP), a redox- active MnSOD mimetic, to mouse primary bone marrow cells or to C57B/L6 mice significantly enhances the number of HSPCs. Mechanistically, MnP reduces superoxide to hydrogen peroxide, which activates intracellular Nrf2 signaling leading to the induction of antioxidant enzymes, including MnSOD and catalase, and mitochondrial uncoupling proteins. The results reveal a novel aspect of ROS signaling in regulating stem cell function, and suggest possible beneficial effects of MnP in treating pathological bone marrow cell loss and increasing stem cell population for bone marrow transplantation, and the development of redox-based therapies.