Prophylactic HPV vaccines hold tremendous potential for reducing cervical and non-cervical HPV-related disease burden worldwide. To maximize on this potential, policy officials will need to carefully consider available evidence, existing uncertainties and the cost–effectiveness of mass HPV vaccination programs in the context of their respective nations and/or regions. Proper harmonization of primary prevention strategies with secondary prevention efforts will also be important. Decisions following such considerations may ultimately depend on programmatic objectives, infrastructure and available resources. Continued research and surveillance surrounding HPV vaccination will be essential for filling current knowledge gaps, and forcing ongoing reconsiderations of selected immunization strategies.