Hematopoietic stem cells (HSCs) and hematopoietic progenitor cells reside in the bone marrow in tissue composed of trabecular bone adjacent to endothelial lined sinuses and surrounded by various stromal cells that include osteoblasts (OB), osteoclasts (OC), chrondrocytes (CC), adipocytes (Ad), and fibroblasts (FB). This tissue also contains a complex environment of extracellular matrix proteins (EMP) and soluble cytokines. The interaction and homeostasis of these stromal components with the HSCs may determine its normal or neoplastic fate after hematopoietic cell transplantation (HCT). Figure 1A illustrates the normal HSC niche in which donor HSCs undergo self-renewal and differentiation to donor progenitor cells (PCs). Figure 1B illustrates the altered environment after HCT in which changes in the balance of extrinsic signals because of chemotherapy and radiation therapy may influence normal donor HSC development toward donor cell leukemia (DCL). These changes after HCT include injured stroma, leaky endothelium, impaired tumor surveillance, and a dysregulated extracellular matrix. Illustration by Kenneth Probst.