Oral mucositis induced by radiation therapy and chemotherapy is a frequently occurring toxicity in patients with cancer. Severe mucositis has a major impact on patient daily functioning,well-being, and quality of life. It can also compromise a patient's ability to tolerate planned therapy, resulting in missed doses or dose reductions. Mucositis negatively affects other health outcomes as well, increasing the risk of opportunistic infections and mortality due to sepsis. It also imposes a significant economic burden, since extended hospitalization and greater analgesic use can substantially increase treatment costs. A five-phase model of the pathobiology of mucositis has been proposed that facilitates our understanding of mucositis pathogenesis and the complex interactions that occur in response to tissue insult. Application of this evolving model has aided in the development of mechanistically based therapies for the prevention and treatment of mucositis. Continued research is needed to optimize when these treatments should be administered during the course of cancer therapy to maximize therapeutic benefit.