Molecular biology of head and neck cancer enables clinicians to personalize treatment based on biomarkers. Oropharyngeal cancer induced by human papillomavirus 16 (HPV-16) typically has a favorable prognosis due to its radiosensitivity and chemosensitivity. However, randomized trials aimed at de-escalating radiation doses or replacing chemotherapy with less toxic agents have not been successful. Discoveries regarding the role of programmed death ligand 1 (PD-L1) on head and neck cancer cells have led to successful treatment with immune checkpoint inhibitors (ICIs) for recurrent disease. Despite this, the optimal sequencing of ICI with radiotherapy remains unclear for the treatment of locally advanced head and neck cancer. Advances in radiation therapy technology and surgical techniques have minimized treatment-related toxicity and may improve patients’ quality of life. The introduction of liquid biopsy enables early detection of cancer recurrence and allows for adaptive drug therapy when the cancer develops resistance to medication. Gene therapy holds great promise, pending resolution of regulatory challenges. Additionally, artificial intelligence is poised to revolutionize head and neck cancer treatment by analyzing large datasets and providing rapid solutions to complex issues.