Oral mucositis is a common toxicity associated with both antineoplastic head and neck radiation and chemotherapy. In addition to exacting a terrible symptomatic toll, mucositis is associated with a number of adverse health and economic outcomes. Furthermore, its presence may compromise the use of optimum agents, doses, or dosing schedules. The current lack of an approved, effective mucositis treatment has sparked interest in the development of interventions that are based on the biological mechanisms that lead to mucosal injury. While our understanding of the molecular and cellular pathways leading to mucositis is still evolving, it is now clear that the condition represents the culmination of a dynamic sequence of events that involve all cells and tissues in the mucosa. Five phases characterize the pathophysiologic progression that results in mucositis: initiation, upregulation and message generation, signaling and amplification, ulceration, and healing. Each phase offers a potential target for therapeutic intervention.