Low level laser therapy (LLLT) has been noted to be effective in mitigating the development of oral mucositis among patients being treated with chemoradiation for cancers of the head and neck. To explain the biological basis for this observation we performed a comprehensive literature search. Our investigation identified a substantial number of LLLT-activated pathways that have been strongly associated with negative tumor outcomes including proliferation, invasion, angiogenesis, metastases and cancer-treatment resistance. In light of these findings, we suggest an investigational strategy to assure that LLLT’s anti-mucositis efficacy is independent of its possible potential to enhance threatening tumor behaviors. Included are appropriate pre-clinical modeling, short- and long-term follow-up of LLLT-treated patients, and the requirement for consistency of LLLT parameters.