During the past two decades, significant advances have been made in the management of patients with rectal cancer. A number of clinical studies have demonstrated the efficacy of preoperative chemoradiation therapy with 5-fluorouracil (5-FU)-based regimens in decreasing local recurrences and improving survival and the likelihood of sphincter preservation. Although 5-FU has been the standard drug used in combination with radiation therapy for many years, new effective drugs including capecitabine, raltitrexed, irinotecan and oxaliplatin have been recently investigated in combination with radiation therapy in the preoperative setting. In addition, novel targeted biological agents including epidermal growth factor receptor inhibitors and vascular endothelial growth factor inhibitors have been shown to enhance the antitumor effect of both radiation and chemotherapy and are currently being explored in initial clinical trials. In the present review we summarize the results of adjuvant therapy. In addition, we will discuss the recently reported phase I-II trials with new drug plus radiation combinations in the preoperative treatment of patients with rectal cancer.