Use of definitive chemoradiation as primary therapy for locoregional squamous cell carcinoma of the anal canal has been the standard approach in the United States since the 1980s. Over the past several years, phase III studies have shown that combination mitomycin C (MMC) and 5-fluorouracil (5-FU) concurrent with radiotherapy had better outcomes than radiotherapy alone or 5-FU with radiotherapy. Two recent phase III studies using diverse treatment strategies showed that cisplatin and 5-FU were not superior to 5-FU and MMC; in one of the trials, use of cisplatin-based chemoradiation resulted in a higher rate of colostomy compared with mitomycin-based chemoradiation. MMC and 5-FU concurrent with radiotherapy remains standard care. Further improvement is likely depending on an increased understanding of the molecular biology of anal carcinoma and the addition of relevant biologic agents to chemoradiation to overcome chemoradiation resistance.