Of the 40 types of human papillomavirus that can infect the mucosal epithelium, four types can now be prevented using prophylactic vaccination. Two of these types (high-risk types 16 and 18) cause 70% of cervical cancers, a proportion of other genital cancers and a subset of head and neck cancers. The low-risk types 6 and 11 cause 90% of genital warts and the disease recurrent respiratory papillomatosis. Thus, if primary HPV vaccination programs can be implemented effectively, the potential for a reduction in global disease burden is great. This article considers the current issues and challenges in delivering primary HPV vaccination programs effectively and the likely impact of the vaccines in both the near and more distant future.