The increasing incidence and mortality rates of HPV-positive cancers, particularly HPV-positive head and neck cancer, in recent years have emphasized the pressing need for more efficacious treatment options. Recent studies have elucidated the molecular distinctions between HPV-positive and HPV-negative cancers, which are crucial for developing precise and effective therapeutic strategies. This review updates the most recent findings on the molecular variances between HPV-positive and HPV-negative cancers, evaluates current treatments for HPV-positive cancers, and summarizes emerging frontiers in HPV-targeted therapies aimed at developing more effective and precise interventions against these cancers.