This chapter discusses management of locally advanced inoperable head and neck cancer, where the terms locally advanced and inoperable have been frequently used interchangeably or together for tumors which present with extensive mucosal involvement, contiguous soft tissue spread and deep muscle infiltration. Multiple factors need to be considered in making treatment choices. Surgical resectability of tumor must be assessed by the surgeon. Availability of reconstructive options and the anticipated functional and cosmetic consequences of surgery impact the choice of therapy. The combination of chemotherapy with radiation is now a viable treatment alternative to surgery. The currently accepted treatment requires concurrent administration of chemotherapy. All chemoradiation regimens have substantial acute toxicity, some more than others. Despite the improvement in locoregional control seen with the use of concurrent chemoradiation, it has also become clear that a significant number of patients continue to be lost to systemic failure.