Head and Neck Squamous Cell Carcinoma (HNSCC) is the seventh most deadly cancer in the world. While traditional therapies are highly morbid, there have been only a few new systemic treatments developed in the last few decades, and these benefit only a small population of patients. The anti-cancer signaling sphingolipid ceramide has shown promise as a therapeutic in many cancer models including preliminary work in HNSCC. The ceramide nanoliposome (CNL) is a nanoscale, therapeutic ceramide-delivery vehicle currently in Phase I clinical trials for treating advanced solid tumors. Thus, the thesis seeks to evaluate the CNL as a potential therapeutic for HNSCC. This is accomplished by exploring methods to circumvent resistance (Chapter 2), identify novel markers of non-canonical cell death (Chapter 3), utilize synergistic dual therapeutic approaches with previously failed EGFR inhibitors (Chapter 4), and manipulate sphingolipid metabolism (Chapter 5). These studies elucidate a myriad of signaling pathways as well as specific druggable targets that can be manipulated to enhance therapeutic efficacy of CNL or other ceramide-based therapies for treatment of HNSCC.