The epidemiology of human papillomavirus (HPV)-associated cancers indicates dramatically increased rates for HPV-related oropharyngeal squamous cell carcinoma (OPSCC) over the past two decades. This development accounts for the increasing significance and research focus in the fields of immunology, oncology, and otolaryngology. In this review, we provide an overview of the most important and recent developments in pathogenesis and therapy in HPV-related OPSCC with a focus on the disease’s immune escape mechanisms and strategies for their reversal. In order to introduce the therapeutic approaches that are currently used and under development, we summarize the viral pathway, genomic alterations, and functional carcinogenesis in relation to antiviral immunity. The different viral strategies to evade the host immune system and their influence in carcinogenesis provide a unique tumor microenvironment that is not completely understood. Immunotherapies under development aim to prevent viral and tumor immunoevasion and may provide new insights into why—despite manifold immunoevasion strategies—an improved clinical outcome can be observed in HPV-related OPSCC.