Concurrent radiotherapy and chemotherapy (5-fluorouracil and mitomycin-C) is established as a sphincter-preserving treatment for squamous cell carcinoma of the anal canal. However, there is room for improvement in rates of tumor control as well as a need to reduce treatment-induced toxicity. Efforts are underway to test the value of newer radiosensitizing chemotherapeutic and molecular targeted agents, as well as to establish the value of advances in radiation therapy planning and delivery. This review discusses the evolution of therapy for anal cancer, from early clinical trials establishing the current standard to more recent studies evaluating cisplatin, capecitabine, oxaliplatin, and cetuximab. Early clinical results from studies incorporating intensity-modulated radiation therapy are also discussed.