Oral mucositis is a common and debilitatingly painful side effect of many forms of chemotherapy and radiation therapy. The erythematous, atrophic, and ulcerative lesions that develop are a consequence of epithelial damage and death mediated through a complex series of molecular and cellular events. The consequences of mucositis are far-reaching and include chemotherapy dose reductions, breaks in radiation treatment, cessation of cancer therapy, reliance on parenteral nutrition, administration of narcotics, hospitalization, and morbidity. In this review, the underlying molecular and cellular pathobiology of oral mucositis is characterized in five phases: initiation, the primary damage response, signaling and amplification, ulceration, and healing. The roles of reactive oxygen species, transduction and transcription pathways, signaling and functional mediators, and bacteria on the development and resolution of mucositis are described as a dynamic process in which epithelial stem cells are the targets. Insights into the mechanisms of oral mucositis are generating new approaches for effective, targeted treatment.