Anal squamous cell carcinoma (SCC) is a rare cancer and accounts for approximately 4% of all cancers of the lower alimentary tract. The dominant etiology is infection with human papilloma virus (HPV), which is the most common sexually transmitted disease in the United States. Integration of HPV DNA into the host genome seems to be the driving mechanism behind carcinogenesis. Vaccines directed against oncogenic HPV serotypes exist, and their utility for preventing anal neoplasia is under investigation. Additional risk factors for developing SCC include HIV infection, anal receptive intercourse, smoking, and immunosuppression. Patients with known anal intraepithelial neoplasia (AIN) must be carefully screened with periodic digital rectal exam and anoscopy. The most common presenting symptom is bleeding, with up to one third of patients presenting asymptomatic. Once tissue diagnosis is made, staging of primary tumor is accomplished with either MRI or transanal ultrasound. Distant disease is evaluated with CT of chest abdomen and pelvis vs whole body PET/CT. The gold standard treatment for stage I-III disease remains the Nigro protocol, first described in 1974. Stage I disease not involving sphincter may be treated with local excision. Distant disease is treated with systemic chemotherapy with radiation reserved for locoregional symptoms. Careful surveillance is mandatory after completion of chemoradiation. Salvage abdominoperineal resection can achieve locoregional control in up to 77% of patients with persistent or recurrent disease. Morbidity is high, mostly owing to wound complications, and as such a flap reconstruction of the perineum is warranted.