Papillomaviruses represent a medically important virus family. Infection with a high-risk human papillomavirus type is a prerequisite for cervical carcinoma development. Infection by low-risk types may result in the generation of benign skin warts. It was recently found that infectious entry of these viruses is dependent upon a specific proteolytic event that occurs prior to viral endocytosis. Specifically, a proprotein convertase, furin or proprotein convertase 5/6, must cleave the minor capsid protein for infection to proceed. Here, an overview of what is currently known about this process is presented, and what we have learned about the papillomavirus lifecycle from these studies discussed. This work also has implications for further advances in papillomavirus vaccine development.