This chapter describes epidemiology, risk factors, anatomy, pathology, screening, clinical presentation, prognostic factors, staging, and treatment paradigm of anal cancer. Approximately 8,600 new diagnoses with 1,400 anal cancer-related deaths in the United States in 2020. Incidence of anal cancer is more than twice as high in females as it is in males. High-risk human papillomavirus DNA has been detected in up to 84% of specimens in large-scale anal cancer studies. Squamous cell carcinoma of the anal canal is a relatively rare but often curable cancer. Other, more rare anal cancers include adenocarcinoma (treated like rectal cancer), melanoma, neuroendocrine, carcinoid, Kaposi’s, leiomyosarcoma, and lymphoma. Other risk factors include HIV infection, history of cervical, vulvar, or vaginal cancer, immunosuppression after organ transplant, smoking, history of receptive anal intercourse. Definitive treatment with concurrent chemoradiation alone is effective treatment for anal cancer.