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On a global scale, at least 20% of human malignancies are caused by known infectious pathogens. Most are viruses; of these, human papillomavirus (HPV) causes more cancers than any other. In populations which do not have herd immunity because of insufficient uptake of the preventive vaccines, HPV infections are endemic, in part, because they are asymptomatic. In the cervix, disease is clinically indolent. In immune- competent persons, a transition from the intraepithelial cancer precursor lesion, cervical intraepithelial neoplasia 3 (CIN3) or high grade squamous intraepithelial lesion (HSIL), to invasive carcinoma is thought to take on the order of 10–15 years. Moreover, not all HSILs progress to cancer; in a relatively short observational window, we and others have reported spontaneous regression of biopsy-confirmed cervical HSIL in a subset of women. The current standard of care treatment is surgical resection. In women who are HIV seropositive, less is known. Persistent infections are common, and the incidence of cervical cancer is three-fold that of immune-competent women.HPV lesions are relatively accessible, thereby providing a clinical setting in which to better understand the immunobiology of disease, and to test proof-of-principle of potential non-surgical interventions. The infectious etiology presents an opportunity to manipulate immune responses to viral antigens. Indeed, the preventative HPV vaccines, Gardasil and Cervarix, are nearly (100%) effective in vaccinated persons. Immune-based therapies for established HPV disease would address two significant clinical settings: (1) in eradicating established cancer precursor lesions (CIN3/HSIL), and (2) in recurrent or metastatic HPV cancers. Early studies have established proof-of-principle in both. Challenges presented in eradicating HPV disease will be discussed, as well as strategies moving forward.