In this chapter, we discuss de-esclation of treatment for patients with HPV-positive disease. We discuss the rationale for de-escalation (why de-escalate?), patient selection criteria (who to de-esclate?) and what the treatment options for de-esclation are and the studies that are currently being run in those areas (how to de-escalate?). We stress the importance of clinicians NOT changing the management of oropharyngeal cancer patients outside clinical trials, and encourage them to recruit to the ongoing studies.