Hematopoietic system transports all necessary nutrients to the whole organism and provides the immunological protection. Blood cells have high turnover, therefore, this system must be dynamically controlled and must have broad regeneration potential. In this review, we summarize how this complex system is regulated by the heme oxygenase-1 (HO-1)—an enzyme, which degrades heme to biliverdin, ferrous ion and carbon monoxide. First, we discuss how HO-1 influences hematopoietic stem cells (HSC) self-renewal, aging and differentiation. We also describe a critical role of HO-1 in endothelial cells and mesenchymal stromal cells that constitute the specialized bone marrow niche of HSC. We further discuss the molecular and cellular mechanisms by which HO-1 modulates innate and adaptive immune responses. Finally, we highlight how modulation of HO-1 activity regulates the mobilization of bone marrow hematopoietic cells to peripheral blood. We critically discuss the issue of metalloporphyrins, commonly used pharmacological modulators of HO-1 activity, and raise the issue of their important HO-1-independent activities.