Cervical cancer and anal cancer share many similarities including causation by oncogenic human papillomaviruses; however, significant differences exist in their epidemiology, risk factors, biologic behavior, management, and treatment. Although rare, the incidence of anal cancer is alarmingly high and continues to increase in high-risk populations, particularly men who have sex with men regardless of their human immunodeficiency virus (HIV) status. There are no national screening guidelines for anal cancer. Using the success of cervical cancer screening as a model, anal cancer screening approaches apply anal cytology, high-resolution anoscopy, and directed biopsy to guide treatment and management strategies. Although much has been learned about the natural history and epidemiology of anal intraepithelial neoplasia (AIN), the rate of progression of high-grade anal intraepithelial neoplasia (HGAIN) to invasive squamous cell carcinomas is not known. The impact of screening and treatment of HGAIN on morbidity and mortality from anal cancer are also unknown. Because the incidence of HGAIN and anal squamous cell carcinoma continue to increase, it is imperative to find pathways for effective screening, early detection, and therapeutic intervention. This article provides an overview of anal cancer screening while highlighting its differences from cervical cancer screening and the remaining obstacles and controversies to implementation of a successful anal cancer screening program. Cancer (Cancer Cytopathol) 2011;. © 2010 American Cancer Society.