Postoperative adjuvant chemoradiotherapy was recommended as the standard treatment for patients with rectal cancer because it reduces local recurrence. This paradigm shifted with the use of neoadjuvant chemoradiotherapy, which not only reduces local recurrence but also improves sphincter preservation and surgical outcomes. However, the treatment of rectal carcinoma remains complicated. The accuracy of tumor staging can be compromised depending on the imaging modality used. The addition of modern chemotherapeutics and biologics to 5-fluorouracil as radiation sensitizers is questionable. Oxaliplatin as a radiation sensitizer has minimal effects on the pathologic complete response, but improves the radiographical response at the expense of an increased risk of toxicities. The role of biologics in addition to radiation therapy continues to be explored. Attention has focused on improving diagnostic imaging, radiation oncology, and surgical techniques, treatment regimens, and on exploring a role of molecular markers for patients with rectal cancers. We review the pivotal trials that have led to the current treatment paradigm for locally advanced rectal cancer and discuss novel methodologies that are being developed for the treatment of this prevalent malignancy.