Squamous cell carcinoma of head and neck (SCCHN) is the most common cancer arising in the head and neck region. Smoking and heavy alcohol drinking are still the well-established causes of most cases worldwide; however, human papillomavirus (HPV) infection is the concerning cause in the Western world. The different pathogenesis, pathophysiology, and prognosis between HPV-driven and non-HPV SCCHN would lead to the different treatment approaches. Breakthroughs in radiation techniques, better organ-preserving surgical strategies, and multidisciplinary management modalities are the major reasons for the curability rate among patients with early and locally advanced SCCHN. Unfortunately, among patients with advanced, recurrent, or metastatic diseases, the treatment remains an area of need. Such patients usually die within a few years. The immune checkpoint inhibitors have been shown to provide astonishingly better survival, but only among a small and not definitely known proportion of patients. Investigating the more specific biomarkers predicting the treatment response and novel therapeutic options is warranted. In this review, we highlight the latest advances in pathophysiology, treatment, and the future direction of researches.