The incidence of anal cancer is increasing in the general population among both men and women. Its incidence is particularly high among certain risk groups such as men who have sex with men and individuals immunosuppressed because of HIV infection. In recognition of the similarity in the biology of anal cancer and human papillomavirus–associated cancer elsewhere in the genital tract, the Lower Anogenital Squamous Terminology project recommended that terminology for lesions be standardized across the anogenital tract, including the anus. Thus, a 2-tier system is recommended, with anal low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesion (HSIL) replacing older terminology. Anal cytology and histopathology use the same 2-tier terminology. Anal LSIL is not believed to be precancerous, whereas HSIL is likely the anal cancer precursor. As at other genital sites, p16 staining is recommended for lesions that are morphologically difficult to distinguish between LSIL and HSIL, and between HSIL and squamous metaplasia when necessary. Performance of anal cytology and high-resolution anoscopy–guided biopsy is performed similarly to procedures in the cervix. Identification and treatment of anal HSIL may reduce the risk of anal cancer, as at other genital tract sites, although this has not yet been formally demonstrated. Likewise, superficially invasive squamous cell carcinoma of the anus is defined similarly to superficially invasive squamous cell carcinoma elsewhere in the genital tract, but the utility of this diagnosis to guide treatment options has not yet been demonstrated.