The management of locally advanced rectal cancer remains a challenge because of relatively high local recurrence rates, even with optimal surgery. This chapter reviews the evidence from clinical trials for the use of various perioperative strategies based on radiotherapy, chemotherapy, or both in these patients, as well as discusses how these results may inform clinical practice. In particular, two treatment strategies that have been shown to be beneficial and that are standard treatment options for patients with locally advanced disease are short-course preoperative radiotherapy and long-course preoperative chemoradiotherapy. In clinical trials in which these treatments were used in addition to surgery, improvements in local recurrence rates have been observed, although overall survival has less frequently been prolonged. These patients should also receive postoperative adjuvant chemotherapy.Other issues that are discussed include the selection of patients with locally advanced disease for treatment, the use of total mesorectal excision as the optimal surgery for these patients, the impact of various preoperative treatments on sphincter preservation rates, and ongoing areas of research in this disease. Although the management of these patients continues to be controversial, it is clear that surgery alone is inadequate for patients with locally advanced rectal cancer and that they are best managed in a multidisciplinary setting.