OBJECTIVE Issues surrounding the prevention and management of severe oral mucositis in patients with head and neck cancer and patients receiving targeted anticancer therapies are reviewed. CONCLUSIONS Cancer therapy-related mucositis is associated with many negative and potentially life-threatening sequelae. Patients receiving chemoradiotherapy for head and neck cancer are at high risk for severe oral mucositis, but there are currently no definitive recommendations on pharmacologic preventive strategies. Recently published evidence on the use of palifermin to combat oral mucositis during chemoradiotherapy for head and neck cancer is encouraging, with two randomized controlled trials indicating an absolute risk reduction of about 15%; however, palifermin use was not associated with lower rates of mucositis-related treatment delays or chemotherapy dosage reductions, and concerns about optimal dosage and cost-benefit issues persist. Oral mucositis due to targeted therapies for renal cell carcinoma and other disorders (e.g., kinase inhibitors, mammalian target of rapamycin inhibitors) is generally less severe than mucositis caused by conventional cytotoxic chemotherapy. For both types of mucositis, recommended management strategies include good oral hygiene and optimal pain control. Research in this area continues to be complicated by investigators' use of varying terminology and mucositis classification schemes. CONCLUSIONS Palifermin appears to reduce the frequency of oral mucositis in patients treated for head and neck cancer, but its place in therapy has not been determined. Although the oral complications of targeted therapies are clinically distinct from those of conventional cytotoxic therapy, the literature recommends similar palliative management strategies for both.