Human papillomavirus (HPV) is one of the most common sexually transmitted infections globally, infecting most sexually active individuals. HPV infection is usually asymptomatic and often transient; however, some infections can persist and cause cancer. In fact, HPV is the main cause of cervical cancer and can also cause cancer of the penis, anus, vagina, vulva, mouth, or throat. Fortunately, there are seven approved vaccines available that are highly effective at preventing infection and HPV-associated cancers. Nevertheless, there is still a need for a better understanding of the mechanisms underlying natural and vaccine-elicited immunity to HPV. Immune responses after natural infection or vaccination encompass both humoral and cell-mediated responses. In natural infection, cell-mediated responses are believed to be responsible for the elimination of virus-infected cells. However, many individuals do not appear to seroconvert following infection. Conversely, vaccination elicits long-lasting antibody levels and robust cell-mediated immune memory. Despite the number of publications on HPV infection and prophylactic vaccine responses, many immune mechanisms, as well as the influence of infection site, remain to be elucidated. In addition, there is an increasing interest to understand the potential role of specific effector functions of antibodies and T cell subsets on vaccine-elicited protection—particularly, how these mechanisms may differ with vaccine type, adjuvant, and dosing schedule. Finally, standardization of relevant immune assessments is critical to facilitate comparisons across studies and new vaccine developments.