Randomized clinical trials have recently established preoperative chemoradiotherapy as the new standard treatment for patients with localized cT3-T4 or N+ rectal cancer. Although its inclusion in the modern multidisciplinary management of patients with rectal cancer makes total eradication of pelvic failure a near reality, it does not yet translate into improved survival. As a result, clinical research should be primarily directed against the micrometastatic process, focusing on integrating innovative strategies, such as upfront chemotherapy before chemoradiation, in subgroups of patients recognized to be at high risk.