Head and neck squamous cell carcinomas (HNSCC) are responsible for over 600,000 new cases, and 380,000 deaths in the world annually. A combination of surgery, radiation (RT), and chemotherapy is used in the multidisciplinary management of patients with locally advanced HNSCC. Despite this aggressive treatment, five-year survival rates with optimal therapy for HNSCC hover around 50%. Response rates to cetuximab (CTX), a monoclonal antibody targeting the epidermal growth factor receptor (EGFR) are <20% when delivered alone and <35% when combined with cytotoxic chemotherapy. Within the radiation field, 30-40% of these patients experience local recurrence. In general, over 50% of patients recur after their initial therapy and 4-26% are diagnosed with metastatic (i.e., incurable) disease, highlighting the unmet need for a better understanding of therapeutic resistance and novel approaches to the treatment of these patients.Autophagy is a cellular process that protects both normal and cancer cells from cellular stress. Autophagy can be activated by harsh conditions such as nutrient deprivation, chemotherapy, or radiation therapy and functions to maintain cellular energy by recycling damaged organelles to generate energy and raw materials to support cell survival. It is our hypothesis that these treatments may be unintentionally activating the autophagic pro-survival process in tumors that would help explain the limited responses seen from patients. The goal of this thesis was to determine the role of autophagy in HNSCC therapeutic resistance and identify improved approaches for the treatment of HNSCC. Both CTX and RT caused a significant increase in autophagy as assessed using the reporter assay and immunoblotting. Higher basal levels of autophagy were found in therapeutic resistant cell lines (UM-SCC1-C5, CTX-resistant cell; MOC2, radiation-resistant cell). Using a clonogenic survival assay, the combination of SAR405 (autophagy inhibitor) and CTX/RT resulted in significant loss of cell survival suggesting a treatment sensitizing effect and indicating the cellular protective role of autophagy in HNSCC tumorigenesis. To bridge the autophagy and clinical relevance, our group generated patient-derived xenograft models to study the LC3B expressions, an autophagy marker, in CTX/RT-resistant patient tissues. It turned out that higher LC3B levels were observed in resistant tissues. Tissue microarray (TMA) was also used to assess the LC3B expression in 107 HNSCC patients with varied stages of tumor, and this data suggests that there are higher LC3B in the recurrent and advanced staged tumors. Knockdown of EGFR and lysosomal-associated transmembrane protein 4B (LAPTM4B), two proteins important in growth-factor deprivation induced autophagy, in CTX-treated but not RT-treated cells showed significant decrease in autophagy. RT did increase the accumulation of ROS (~50%), leading to the increased autophagy in HNSCC by two times. RT-induced mitochondrial autophagy (mitophagy) as confirmed by knockdown of Pink1, a critical mediator of mitophagy. In vivo, SAR405 treatment improved tumor control when combined with CTX/RT when compared to single treatment. Taken together, our findings suggest that inhibition of autophagy can improve the efficacy of anticancer treatments and suggest that future drugs which target specific subtypes of autophagy may be needed to personalize treatment combinations for HNSCC patients.