Head and neck squamous cell carcinomas are a group of malignancies that are sensitive to systemic therapy, in part due to the complexity of the molecular aberrations in these malignancies that impair DNA repair mechanisms. Administration of chemotherapy in the treatment of head and neck cancers is guided by treatment goals and patient factors unique to this patient population. The known radiation sensitizing properties of chemotherapy and its ability to impact rates of distant failure have established concurrent chemoradiation as a standard definitive and adjuvant therapy for locally advanced disease. Although known to produce tumor responses, chemotherapy given in the metastatic setting has not been consistently demonstrated to improve overall survival. The combination of chemotherapy with targeted monoclonal antibodies has shown promising results. Future investigation of the role of nonoperative treatments in this disease will likely focus on efforts to decrease late treatment-induced morbidity, exploration of reirradiation with concurrent chemotherapy as a salvage therapy, and further integration of chemotherapy, radiation and targeted therapies in both definitive and palliative management.