Human papillomavirus (HPV) infection is now established as a major etiologic factor for oropharyngeal cancers. Case-control studies conducted around the world show strong and consistent associations of markers of HPV exposure with risk of oropharyngeal cancers (range of odds ratios [OR] for oral oncogenic HPV infections = 3.6-230.0, ORs for HPV16 L1 antibodies = 2.3-182.0, and ORs for HPV16 E6/E7 antibodies = 9.2-231.0. HPV-positive oropharyngeal cancers are epidemiologically distinct from HPV-negative ones, and are characterized by younger age at onset, male predominance, and strong association with sexual behaviors. Importantly, HPV-positive oropharyngeal cancer patients have substantially improved outcomes (28-80 % reductions in the risk of death) than HPV-negative patients. Given the superior survival, younger age, and good performance status of HPV-positive oropharyngeal cancer patients, de-intensified therapies are currently being considered for this group of patients. Recent analyses of cancer registry data show dramatic increases in incidence of oropharyngeal cancers during the past 15-20 years in several parts of the world, highlighting the need for prevention strategies. If proven efficacious, currently available prophylactic HPV vaccines hold great promise for primary prevention of HPV-associated oropharyngeal cancers.