Cervical cancer incidence and mortality have decreased in high-income countries, but low- and middle-income countries continue to bear a significant burden from the disease. Human papillomavirus (HPV) vaccines are a promising alternative for disease control; however, their introduction is slow in settings with greater need. We conducted a review of HPV vaccine efficacy and effectiveness reported in clinical trials and population-based studies. Efficacy of HPV vaccines is close to 100% when using a three-dose schedule in HPV-negative young women (<25 years old) for protection against persistent infection and HPV vaccine-type associated pre-cancerous lesions. Furthermore, sustained protection for up to 12 years of follow-up has been demonstrated; cross-protection against non-vaccine types is particularly observed for the bivalent vaccine, and preliminary data regarding impact on invasive cancer have emerged. Given its lower efficacy, catch-up vaccination beyond 19 years of age and proposals for vaccinating adult women deserve careful evaluation in accurately designed studies and economic analyses. Despite positive results regarding immunogenicity and post-hoc analysis for cervical intra-epithelial neoplasia in clinical trials, population-based data for prime and booster two-dose schedules are not available. Evaluation of vaccine safety from surveillance systems in immunization programs that have already distributed more than 270 million doses found no association of HPV vaccination with serious side effects. The introduction of HPV vaccination in national immunization programs remains the main challenge in tackling the burden of cervical cancer (up to 2018, only 89 countries have introduced vaccination worldwide, and most of these are high-income countries). Access models and technical capacity require further development to help low- and middle-income countries to increase the pace of vaccine delivery. Alternative approaches such as one-dose schedules and vaccination at younger ages may help reduce the programmatic and economic challenges to adolescent vaccination.