Human papillomavirus (HPV) is the necessary cause of cervical cancer, the fourth most common cancer and cause of cancer-related death in females worldwide. HPV also causes anal, vaginal, vulvar, penile, and oropharyngeal cancer. Prophylactic HPV vaccines based on recombinantly expressed virus-like particles have been developed. Two first-generation, U.S. Food and Drug Administration (FDA)-approved vaccines prevent infections and disease caused by HPV16 and HPV18, the two HPV genotypes that cause approximately 70% of cervical cancer, and one of these vaccines also prevents HPV6 and HPV11, the two HPV genotypes that cause 90% of genital warts. A next-generation vaccine, recently approved by the U.S. FDA, targets HPV16, HPV18, and five additional HPV genotypes that together causes approximately 90% of cervical cancer as well as HPV6 and HPV11. In clinical trials, these vaccines have shown high levels of efficacy against disease and infections caused by the targeted HPV genotypes in adolescent females and males and older females. Data indicate population effectiveness, and therefore cost effectiveness, is highest in HPV-naive young females prior to becoming sexually active. Countries that implemented HPV vaccination before 2010 have already experienced decreases in population prevalence of targeted HPV genotypes and related anogenital diseases in women and via herd protection in heterosexual men. Importantly, after more than 100 million doses given worldwide, HPV vaccination has demonstrated an excellent safety profile. With demonstrated efficacy, cost-effectiveness, and safety, universal HPV vaccination of all young, adolescent women, and with available resources at least high-risk groups of men, should be a global health priority. Failure to do so will result in millions of women dying from avertable cervical cancers, especially in low- and middle-income countries, and many thousands of women and men dying from other HPV-related cancers.