The resistance of some head and neck squamous cancers (HNSCC) to standard radiation therapy led to the investigation of altered fractionation regimens and the integration of chemotherapy aimed at improved therapeutic outcomes. Intensive clinical investigations during the last 3 decades have shown the benefits of biologically sound altered fractionation and concurrent chemoradiation regimens in improving local-regional control and less consistently the overall survival. These results have contributed to redefining the standard of care. The results of large randomized trials are reviewed and summarized in this article, along with recommendations for treatment selection. In view of all available data, it is proposed that the current standard nonsurgical therapy is the conventional once-daily radiotherapy alone for T1 and favorable T2, N0-1 tumors; altered fractionation alone for unfavorable T2 or exophytic T3, N0-1 disease; radiation with planned neck dissection for T1-2N2-3 tumors; and concurrent chemoradiation for more advanced HNSCCs. These newer options offer the unprecedented opportunity to select the proper therapy based on patient and tumor features and the expertise of the oncology team with the goal of optimizing cancer control and functional outcomes. Meanwhile, research efforts are ongoing to refine chemoradiation regimens and schedules, to address toxicity amelioration, and to identify predictive biomarkers and effective molecularly targeted therapy. These initiatives will likely lead to improvement in the therapeutic index for patients with HNSCC.