Head and neck squamous cell carcinoma of unknown primary (SSCUP) presents a clinically challenge disease process requiring elaborate multidisciplinary collaboration for effective treatment. With the rise in prevalence HPV associated squamous cell carcinoma, it has become the predominant etiology SCCUP of the head and neck. Advances in the diagnostic evaluation and treatment of SCCUP have led to higher detection rates of primary lesions, improved disease-free and overall survival outcomes, and reduced morbidity for patients. Furthermore, delineation of the molecular implications of HPV positivity and disease behavior has opened avenues for successful de-escalation of treatment. Transoral robotic surgery (TORS), as well as dose reduction protocols show significant promise for oncologic efficacy with minimization of treatment related morbidity.