Oral mucositis is a painful ulceration of the mucosal lining of the oropharynx. It occurs frequently in patients receiving radiation therapy and/or chemotherapy for solid tumors and has been reported in up to 98% of patients undergoing hematopoietic stem cell transplantation. The development of mucositis is associated with significant morbidity, including longer hospital stays, increased bacteremia, and pain that interferes with talking, eating, and sleeping. Palifermin, a recombinant humanized keratinocyte growth factor, is the first pharmacologic agent that has been Food and Drug Administration-approved to decrease the incidence and duration of mucositis in patients with hematologic malignancies receiving chemotherapy requiring hematopoietic stem cell transplantation support. Results from phase I/II trials suggest that it might also benefit patients receiving treatment for solid tumors; however, the results from ongoing phase III trials will need to be available and examined before it can be incorporated into general clinical practice for this patient population.