Persistent infection with oncogenic human papillomavirus (HPV), leading to precancerous lesions and potentially cervical cancer, is a serious health burden. The natural history of infection is one that enables the virus to remain immunoevasive within the cervical epithelium and persist for decades. Many studies have provided important information on why some women clear infection and why others do not. The infectious process of HPV may be affected by many cofactors, adding to the complexity of disease development. Vaccination against oncogenic HPV along with cervical screening are two methods that have been developed to provide protection and eliminate the overall burden of disease in women. This article highlights the natural history of oncogenic HPV infection of the cervix and the limitations that currently exist on the literature. © 2009 by The American College of Obstetricians and Gynecologists.