Abstract: Ionizing radiation can induce a severe and persistent reduction in the structural integrity of skeletal tissue. With improved cancer survivorship, preventing the morbidity and mortality associated with treatment-induced late health effects is becoming a great concern. The skeletal damage observed late after exposure include fractures of bone at sites that absorb dose during cancer treatment, joint failure and arthropathy in adult survivors of cancer, avascular necrosis, among others. Our research focuses on the cause, extent, and progression of damage to joints (e.g., bone and articular cartilage) after exposure to ionizing radiation. Bone damage has historically been thought to result from a low turnover state (reduced bone formation due to damaged osteoblasts) that is persistent through time. Our preclinical and clinical models have identified an early increase in osteoclast activity as a substantial contributor to bone loss and fracture. The increase in osteoclast activity also serves as a potential therapeutic target. Cartilage is generally considered a radioresistant tissue. While arthropathies have been reported from various joints exposed to radiation after cancer therapy or following occupational exposures, the damage is typically attributed to nearby bone fractures. However, exposure of primary human and porcine chondrocytes and explants to ionizing radiation lowers glycosaminoglycan synthesis; increases matrix degradation; is associated with elevated MMP and ADAMTS 5 production; and impairs IGF-1 signaling. These changes are observed within the first week of exposure. Radiation can directly affect bone and cartilage structure and function, and while these tissues are considered to be “late-responders”, many effects are observed early. Identifying the cellular mechanisms underlying how these tissues respond to radiation through time is crucial for the development of therapeutics and mitigation of late skeletal injury.