New vaccines designed to prevent human papillomavirus (HPV) infection have the potential to reduce the incidence of serious illness and death worldwide among women, substantially reduce the emotional suffering associated with abnormal Papanicolaou (Pap) test results and the diagnosis of cervical cancer, and save significant health care dollars. However, these benefits may not be fully realized until the vaccine is accepted by patients, parents, and health care practitioners. Furthermore, there may be unique issues related to the acceptance of a vaccine designed to prevent a sexually transmitted infection that is poorly understood by many women. Among the acceptance issues are: individual comfort with a sexually transmitted infection (STI) vaccine; parental comfort with vaccination of their preadolescent/early adolescent daughters; physician comfort with recommending a human papillomavirus vaccine to women and parents of preadolescents; and physician communication skills related to talking with women and parents about the vaccine. Potentially difficult as it might be to implement a vaccination program, vaccination and prevention of HPV-associated disease are still infinitely preferable to observation and treatment. This article will review some of the potential barriers to HPV Vaccine acceptance, with a particular focus on factors relevant to female patients, parents, and health care providers.