Head and neck cancer is the seventh most common cancer globally, with approximately 900,000 new cases every year and a 50% mortality rate. Major risk factors for head and neck cancers include tobacco, alcohol, viral infections like human papillomavirus and Epstein-Barr virus, and genetic alterations. Despite the recent advancements in current treatment options like surgery, radiation therapy, chemotherapies, targeted therapies, and immunotherapies, the clinical and molecular heterogeneity of head and neck cancers makes any treatment challenging and often found to be associated with considerable side effects. In this context, personalized medicine has emerged as an effective therapeutic choice that enables medical professionals to customize treatments depending on genetic variations of an individual, resulting in better patient outcomes and fewer side effects. Recent advances in next-generation sequencing and molecular profiling, along with the developments in diagnostic methods, have revolutionized the identification of specific genetic traits/mutations and/or epigenetic biomarkers to customize medical choices and treatment procedures for individual patients. This chapter explores the recent advancements in personalized medicine for head and neck cancer treatment, highlighting targeted therapies, immunotherapies, gene therapies, and stem cell therapies. Furthermore, the prospects and challenges of using personalized medicine in head and neck cancer are also discussed.