Among head and neck squamous cell carcinoma (HNSCC), the incidence of oropharyngeal SCC (OPSCC) is increasing in contrast to carcinoma with origin in other subsites. Human papillomavirus (HPV) is now recognized as a significant risk factor of the carcinogenesis of OPSCC. The HPV-related OPSCC patients tend to be relatively young, less exposed to tobacco and alcohol, and have a relatively high socioeconomic status and education level, which is distinct from HPV-unrelated classical OPSCC. The neck metastases tend to be aggressive and cystic. The better response to treatment resulting in improved prognosis of HPV-related OPSCC led to reconsidering the clinical staging and treatment approaches. Clinical trials of treatment deintensification to reduce the acute and late toxicity without compromising efficacy have been conducted. This review of HPV-related OPSCC focuses on current and generally accepted facts regarding the biology, epidemiology, and therapeutic strategy of this new disease entity.