Squamous cell carcinoma of the anus (SCCA) is a rare tumor. However, its incidence has been increasing in men and women over the past 25 years worldwide. Risk factors associated with this cancer are those behaviors that predispose individuals to human papillomavirus (HPV) infection and immunosuppression. Anal cancer is generally preceded by high-grade anal intraepithelial neoplasia (HGAIN), which is most prevalent in human immunodeficiency virus-positive men who have sex with men. High-risk patients may benefit from screening. The most common presentation is rectal bleeding, which is present in nearly 50% of patients. Twenty percent of patients have no symptoms at the time of presentation. Clinical staging of anal cancer requires a digital rectal exam and a positron emission tomography/computed tomography scan of the chest, abdomen, and pelvis. Endorectal/endoanal ultrasound appears to add more-specific staging information when compared with digital rectal examination alone. Treatment of anal cancer prior to the 1970s involved an abdominoperineal resection. However, the current standard of care for localized anal cancer is concurrent chemoradiation therapy, primarily because of its sphincter-saving and colostomy-sparing potential. Studies have addressed alternative chemoradiation regimens to improve the standard protocol of fluorouracil, misogynic, and radiation, but no alternative regimen has proven superior. Surgery is reserved for those patients with residual disease or recurrence.