Bone fractures greatly decrease an individual’s quality of life, as well as increase an individual’s risk for further complications, including death. Ionizing radiation causes bone loss, leaving bones at increased risk of fracture. This exposure, particularly in the context of cancer patients receiving radiotherapy, results in damage to normal (nontumor) tissue. Inflammation is a common response to radiation-induced tissue damage, characterized by increased presence of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNFα. However, little is known about the roles of these cytokines in radiationinduced bone loss. This thesis hypothesized that the up regulation of pro-inflammatory cytokines (IL-1β, IL-6, and TNFα) after irradiation would lead to rapid activation of osteoclasts and subsequent bone loss. Three approaches were used to investigate the roles of these cytokines in radiation-induced bone loss: 1) Rodent models deficient in IL-1β receptor, IL-6, TNFα, and TNFα/IL-1β receptor combined; 2) Administration of TNFbinding protein (Enbrel), IL-1 receptor antagonist (Kineret), or a combination of the two; 3) Administration of a p38 blocking molecule (AR-447). Irradiation did result in a decline of bone volume and overall deterioration of micro-architecture within the first few weeks after exposure. Additionally, pro-inflammatory cytokine presence and expression were elevated at early time points after exposure. However, using IL-1β, IL-6, and TNFα knockout mouse strains or applying agents that block the activity of these cytokines did not prevent bone loss after radiation exposure. Providing an inhibitor of p38 activity, an important upstream and downstream mediator of pro-inflammatory cytokine production, likewise did not prevent radiation-induced osteoporosis. Therefore, within the confines of these animal studies, pro-inflammatory cytokines did not play a significant role, if any role at all, in radiation-induced bone loss, suggesting the possibility that these cytokines are not responsible for the radiation-induced activation of osteoclasts.