Background Cervical cancer remains a major cause of cancer death in women worldwide. Moreover, human papillomavirus (HPV)-related disease of the urogenital tract (including preinvasive and invasive cervical, vaginal, vulvar, penile, and anal disease) remains a major cause of morbidity and mortality in the United States and internationally. Objective The goal of this article was to review the vaccines available as well as the major Phase III trials of the quadrivalent and bivalent vaccines for the prevention of HPV-related genital tract disease. Methods A literature search was performed through PubMed using the terms "HPV vaccination" and limited to clinical trials over the last 6 years. The most relevant and largest scale trials were included in this report. Results Prophylactic vaccination has emerged as an important tool that holds promise in decreasing the burden of HPV disease. However, HPV vaccination is known to be largely type-specific. Vaccination is most effective when administered at a younger age and before sexual activity and exposure to HPV. Large trials have been conducted and show efficacy of both the bivalent (HPV types 16 and 18) and quadrivalent (HPV types 6, 11, 16, and 18) vaccine in the prevention of preinvasive lesions and infection with these HPV types. Conclusions Future directions include development of more affordable vaccines with extended HPV-type coverage as well as implementation of feasible worldwide vaccination programs. © 2014 Elsevier HS Journals, Inc. All rights reserved.