Significant gains have been achieved in the integration of radiation therapy (RT) and chemotherapy with surgery in the management of patients with localized rectal cancer. Treatment combinations of RT and chemotherapy with surgery have evolved to neoadjuvant approaches of these modalities to enhance sphincter preservation, tumor control, and reduction of acute and late treatment-related morbidity. Although 5-fluorouracil (5-FU)-based chemotherapy in combination with RT remains the standard adjuvant therapy for rectal cancer, the integration of novel chemotherapeutic agents and biologic modulators is being actively investigated.