Surgery remains the mainstay of treatment for colorectal cancer. Although the role of radiation therapy in colon cancer is unclear, its role in the management of locally advanced rectal cancer has been extensively studied in clinical trials. The use of postoperative chemoradiotherapy has been shown to improve local control and disease-free survival in patients with locally advanced disease over surgery alone; however, an overall survival advantage remains unproven. Clinical trials evaluating preoperative radiotherapy have demonstrated an improved local control as well as a survival advantage. Randomized studies comparing preoperative versus postoperative combined-modality approaches have failed in the United States, mainly due to the perceived advantages of preoperative treatment: improved patient tolerance, tumor downstaging, and fewer treatment-related complications. While 5-fluorouracil—based chemotherapy remains the standard systemic agent used along with radiation, other novel agents and strategies have recently been developed and are under investigation. In this review, we discuss the use of novel anticancer agents in combination with radiation therapy for the treatment of locally advanced rectal cancer.