Oral mucositis (OM) remains a major side effect of various cancer therapies, which exacts a significant price in terms of morbidity and cost of care. Efforts aimed at prevention and/or therapy of OM have been largely unsuccessful. Few agents have shown efficacy, and even those were applicable to limited types of patients. The advent of small-molecule targeted agents opened new possibilities for intervention in the mucopathogenic processes induced by cancer therapies. One of these agents, recombinant human keratinocyte growth factor (KGF), has been studied extensively and has shown promising results in reducing chemotherapy induced OM. This drug's effects on stem cell engraftment, graft-versus-host disease and other treatment-induced morbidities remain undefined. In this article we evaluate the pre-clinical and clinical evidence and discuss the clinical applications of KGF as an adjunct therapeutic agent in oncology. © 2009 Barasch et al, publisher and licensee Dove Medical Press Ltd.