Persistent human papillomavirus (HPV) infection is the central cause in the development of anogenital warts, precancers and cancers of uterine cervix, and a major factor in the genesis of other malignancies of the lower anogenital and upper aerodigestive tracts. The burden of disease carries very high medical, financial and psychosocial costs. The role of prophylactic HPV vaccines in reducing the burden of disease is discussed in light of the results of multiple randomized, controlled trials conducted worldwide in thousands of young females. The review discusses some of the issues that are still unknown, with respect to long-term vaccine performance, challenges to be overcome to achieve universal, mass prophylactic HPV vaccination, as well as the potential impact of the vaccines on primary screening for, and management of, HPV-related anogenital infection and disease.