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Oral mucositis is a clinically important and sometimes dose-limiting complication of cancer therapy. Mucositis lesions can be painful, affect nutrition and quality of life, and have a significant economic impact. The pathogenesis of oral mucositis is multifactorial and complex. The present review discusses the morbidity, economic impact, pathogenesis, and clinical course of mucositis. Current clinical management of oral mucositis is largely focused on palliative measures such as pain management, nutritional support, and maintenance of good oral hygiene. However, several promising therapeutic agents are in various stages of clinical development for the management of oral mucositis. These agents are discussed in the context of recently updated evidence-based clinical management guidelines.