Radiotherapy and chemotherapy are commonly used or treatment of cancer. Unfortunately, these treatments frequently cause acute and/or long-term bone marrow (BM) injury that can adversely affect the quality of life and the course of treatment. Our recent studies suggest that induction of hematopoietic stem cell (HSC) senescence by ionizing radiation (IR) and certain chemotherapeutic agents may contribute to long-term BM injury by impairing the ability of HSCs to self-renew. This suggestion is in agreement with a growing body of evidence demonstrating that HSCs from Bmi-1(-/-) and ATM(-/-) mice can lose their ability to self-renew by undergoing premature senescence. Interestingly, IR and different chemotherapeutic agents may induce HSC senescence and long-term BM injury in an agent-specific manner by activation of the p53-p21 and/or p16-Rb pathways. It will be of a great interest to determine if inhibition of these pathways can ameliorate radiotherapy and chemotherapy induced long-term BM injury.