Patients with locally recurrent head and neck cancer previously treated with radiation have a poor prognosis. Administration of a second course of radiation to tissues within a previous radiation portal, has been traditionally considered unsafe. Survival rates of highly selected patients treated with concurrent chemotherapy and re-irradiation may be as high as 25% at 2 years--exceeding the outcome of matched historical controls treated with chemotherapy alone (10%). However, many questions exist regarding the use of re-irradiation. Uncertainty exists over the criteria for selecting patients who are most appropriate for treatment with re-irradiation. Even greater concern exists regarding toxicity and functional sequelae associated with the use of re-irradiation. Whether the benefits of re-irradiation on locoregional disease control and survival outweigh its potentially severe and life-threatening adverse effects is not clear. In this review, we will discuss re-irradiation and other treatment options for squamous cell carcinoma patients with previously irradiated, locoregional recurrent or second primary tumors in the head and neck, and describe a recently initiated randomized trial comparing chemotherapy plus re-irradiation with chemotherapy.