Squamous cell carcinoma (SCCA) of the anal canal is an underrecognized malignancy that is growing in annual incidence. Over the years, combined chemoradiation has been the mainstay of treatment for locally advanced SCCA of the anal canal. Currently, the human papilloma virus (HPV) vaccine is recommended to prevent the development of HPV and its associated precancerous lesion(s). Patients diagnosed with the human immunodeficiency virus (HIV+) are prone to develop anal cancer due to their high risk of contracting HPV infection. We will focus on the development and management of SCCA of the anal canal (both localized and metastatic), including special details on HIV-positive patients. Highlights will include the role of targeted therapy based on available literature. Our objective is to aid practicing physicians in formulating a treatment plan for both locally advanced and metastatic patients.