Immunotherapy approaches for head and neck squamous cell carcinoma (HNSCC) are rapidly advancing. Human papillomavirus (HPV) has been identified as a causative agent in a subset of oropharyngeal cancers (OPC). HPV-positive OPC comprises a distinct clinical and pathologic disease entity and has a unique immunophenotype. Immunotherapy with anti-PD1 checkpoint inhibitors has exhibited improved outcomes for patients with advanced HNSCC, irrespective of HPV status. To date, the clinical management of HPV-positive HNSCC and HPV-negative HNSCC has been identical, despite differences in the tumor antigens, immune microenvironment, and immune signatures of these two biologically distinct tumor types. Numerous clinical trials are underway to further refine the application of immunotherapy and develop new immunotherapy approaches. The aim of this review is to highlight the developing role of immunotherapy in HPV-positive HNSCC along with the clinical evidence and preclinical scientific rationale behind emerging therapeutic approaches, with emphasis on promising HPV-specific immune activators that exploit the universal presence of foreign, non-self tumor antigens.