Human papillomavirus (HPV) is now recognized as the primary cause of increased incidence of a subset of head and neck squamous cell cancers (HNCs) globally. Recent studies highlight the importance of understanding the epidemiology of HPV-positive HNCs to develop effective public health interventions. The article reviews data on incidence trends, the global HPV-attributable fraction, sex disparities in cancer risk, the latency period between infection and cancer, the potential impact of HPV vaccination, and the prospects for secondary prevention through screening for oral HPV infection or seroreactivity to viral antigens. The incidence of oropharyngeal cancer (OPC) has increased globally, particularly in North America and northern Europe. In Taiwan, OPC rates increased sharply from 1995 to 2009. Worldwide cancer registry data show that OPC incidence rates were higher and increased more sharply among men than women. These trends suggest a role of HPV in increasing OPC incidence among men, while smoking is a dominant factor for women. Several molecular studies have demonstrated that HPV is responsible for the observed increase in OPC incidence. Meta-analyses show a significant increase in HPV prevalence in OPC over time. In the United States, HPV prevalence in OPC increased from 20.9% before 1990 to 65.4% after 2000. In Australia, HPV DNA-positive OPC increased from 1995 to 2010. In the Netherlands, HPV DNA-positive OPC increased from 5.1% to 29.0% between 1990 and 2010. The HPV-attributable fraction for OPC is estimated to be 45.8%, with higher rates in North America and northern Europe. The proportion of OPCs testing positive for HPV increased over time. However, the true increase in HPV-positive OPC incidence is difficult to determine without considering the impact of smoking. Risk factors for HPV-positive OPC include sexual behavior, with a higher number of oral sexual partners associated with increased risk. Oral HPV infection is the principal risk factor for HPV-positive OPC, and most oral HPV infections are sexually acquired. The prevalence of oral HPV infection is higher among men than women, and the prevalence increases with more oral sexual partners. The latency period between HPV infection and cancer development is estimated to be 10 to 30 years. Prophylactic HPV vaccines are highly effective in preventing HPV infections and associated anogenital precancerous lesions. However, their effectiveness against oral HPV infection and related diseases is not well established. Screening for HPV-positive OPC is currently infeasible due to the inability to detect precursor lesions and the lack of established interventions to reduce cancer incidence or mortality. The identification of a single necessary cause for cancer provides a rare opportunity for public health interventions. Prophylactic HPV vaccination holds promise in reversing incidence trends after 2060. However, without clinical trialHuman papillomavirus (HPV) is now recognized as the primary cause of increased incidence of a subset of head and neck squamous cell cancers (HNCs) globally. Recent studies highlight the importance of understanding the epidemiology of HPV-positive HNCs to develop effective public health interventions. The article reviews data on incidence trends, the global HPV-attributable fraction, sex disparities in cancer risk, the latency period between infection and cancer, the potential impact of HPV vaccination, and the prospects for secondary prevention through screening for oral HPV infection or seroreactivity to viral antigens. The incidence of oropharyngeal cancer (OPC) has increased globally, particularly in North America and northern Europe. In Taiwan, OPC rates increased sharply from 1995 to 2009. Worldwide cancer registry data show that OPC incidence rates were higher and increased more sharply among men than women. These trends suggest a role of HPV in increasing OPC incidence among men, while smoking is a dominant factor for women. Several molecular studies have demonstrated that HPV is responsible for the observed increase in OPC incidence. Meta-analyses show a significant increase in HPV prevalence in OPC over time. In the United States, HPV prevalence in OPC increased from 20.9% before 1990 to 65.4% after 2000. In Australia, HPV DNA-positive OPC increased from 1995 to 2010. In the Netherlands, HPV DNA-positive OPC increased from 5.1% to 29.0% between 1990 and 2010. The HPV-attributable fraction for OPC is estimated to be 45.8%, with higher rates in North America and northern Europe. The proportion of OPCs testing positive for HPV increased over time. However, the true increase in HPV-positive OPC incidence is difficult to determine without considering the impact of smoking. Risk factors for HPV-positive OPC include sexual behavior, with a higher number of oral sexual partners associated with increased risk. Oral HPV infection is the principal risk factor for HPV-positive OPC, and most oral HPV infections are sexually acquired. The prevalence of oral HPV infection is higher among men than women, and the prevalence increases with more oral sexual partners. The latency period between HPV infection and cancer development is estimated to be 10 to 30 years. Prophylactic HPV vaccines are highly effective in preventing HPV infections and associated anogenital precancerous lesions. However, their effectiveness against oral HPV infection and related diseases is not well established. Screening for HPV-positive OPC is currently infeasible due to the inability to detect precursor lesions and the lack of established interventions to reduce cancer incidence or mortality. The identification of a single necessary cause for cancer provides a rare opportunity for public health interventions. Prophylactic HPV vaccination holds promise in reversing incidence trends after 2060. However, without clinical trial