Anal cancer is a rare disease, accounting for 2.8% of all gastrointestinal tract malignancies and 0.5% of all new cancer cases in the United States. In certain high-risk populations, however, the incidence is significantly higher, and continues to rise, having risen by 2.7% per year from 2001 to 2015 in patients 50 years and older. While anal malignancies reflect the multiple histologic subtypes found in the anal canal and include adenocarcinomas and malignant melanomas, the large majority are squamous cell carcinomas, and these are the focus of this chapter.