Human papillomavirus virus-like particle (HPV VLP) HPV vaccines currently evaluated for licensing are likely to be available soon. Licensure will be based on evidence that the vaccine is well tolerated and provides near complete type-specific protection against HPV infections and their resulting lesions in the first few years after vaccination. Several important questions will remain to be answered after licensure to guide vaccine implementation and to permit the rational evaluation of vaccination in cancer prevention programs. These include the long-term safety and efficacy of vaccination, the optimal ages for vaccination, efficacy against HPV types not included in the vaccine and against existing infections, and efficacy in males. Modulators of vaccine efficacy (e.g., HIV infection) and immune mechanisms of long-term protection also remain to be defined. The real-world effectiveness of vaccination programs will need to be assessed. Issues related to the implementation of a vaccine that targets pre-adolescents and early adolescents and to the acceptability of a cancer vaccine targeted against a sexually transmitted infection will need to be understood before vaccination programs can be successful. It is hoped that continued improvements to the current HPV vaccines will lead to the introduction in future years of second generation vaccines that simplify delivery and/or expand its coverage. Finally, the natural history of HPV types not covered in the candidate vaccines will need to be carefully studied following vaccination. Public health authorities in various countries will play a pivotal role in determining if these questions are answered in a timely manner.