Background <p>Hematopoietic stem cells (HSCs) are the lifelong source of hematopoietic cells, maintained within the specialized microenvironment of the bone marrow. A central question remains regarding the mechanisms that regulate HSC maintenance. Functional studies have advanced our knowledge of the HSC niche, which consists of perivascular stromal, skeletal, and endothelial cells. Understanding the HSC niche is particularly important in the context of myeloablation which disrupts both the hematopoietic cells and their supporting microenvironment. As a clinical intervention, myeloablation followed by HSC transplantation is a well-established treatment option that has been shown to improve prognosis and increase survival in patients. These positive outcomes result from the reconstitution of the hematopoietic system by transplanted HSCs with the support of the regenerated microenvironment.</p> Objective <p>Recent studies have made significant progress in understanding the plasticity of the bone marrow microenvironment. This review provides an overview of recent findings on the HSC niche during homeostasis and after myeloablative stress.</p> Conclusion <p>Despite the advances made, it is still unclear how the bone marrow microenvironment adjusts and regenerates after stress. Further advances in understanding HSC niche regeneration could have important implications for patient care.</p>