Total body irradiation (TBI) is a critical component of conditioning regimens in hematopoietic stem cell transplantation (HSCT), bridging the realms of hematologic oncology and radiation oncology. TBI in HSCT serves a dual purpose: eradicating residual malignant cells and creating an immunosuppressive environment to facilitate engraftment of donor hematopoietic stem cells. The success of TBI-based conditioning regimens hinges on precise dosimetry, fractionation, and optimization of therapeutic ratios to balance therapeutic efficacy and normal tissue tolerance. TBI is an integral part of curative treatment for diseases like acute leukemia, lymphoma, and myeloma, and offers the potential for long-term disease control and durable remissions. The acute and long-term toxicities need to be monitored and addressed. This chapter also discusses the role of various radiotherapy regimes in hematologic malignancies, specifically leukemias (cranial, craniospinal, testicular, splenic, and ocular).