With optimized local treatment, achieved in the last years by TME surgery and the shift from a postoperative to a preoperative treatment approach, distant metastases have become the predominant mode of failure in rectal cancer. Therefore, the intensification of chemotherapy seems essential to improve distant control and survival in rectal cancer. The integration of newer generation chemotherapeutics and target agents into fluoropyrimidines-based chemoradiotherapy (CRT) has been the more actively pursued intensification strategy. However, early results from randomized phase III trials, evaluating the addition of oxaliplatin to preoperative fluoropyrimidines-based CRT, did not show a significant impact on early pathological response with the addition of oxaliplatin, with the exception of the German CAO/ARO/AIO-04 study. Moreover, the integration of target agents into preoperative CRT, although attractive in principle, has yielded low rates of pathologic complete responses when combined with cetuximab and some concerns on surgical morbidity following preoperative treatment with bevacizumab have been raised. Several novel strategies with different sequence of multimodal treatment components have been developed. However, the evidence that rectal cancers are a widely heterogeneous group of tumors with different prognostic implications, has indicated that the careful assessment of the risk of recurrence is a critical issue. In the era of the preoperative approach, staging with MRI, for its ability to predict the involvement of the mesorectal fascia, should be mandatory for all patients with rectal cancer, to refine the selection of patients for different treatment strategies. Moreover, considering that response to preoperative treatment is not uniformly obtained in all patients and post-operative chemotherapy is generally met with poor adherence, a risk-adapted strategy should be pursued in the postoperative setting as well. The selection of patients for different multidisciplinary treatment strategies based on clinico-pathological features, rather than the current "one size fits all" approach, will allow minimizing therapy and maximizing outcome for rectal cancer patients.