Colorectal cancer is the third most common cause of cancer deaths worldwide. The management of rectal cancer has undergone, and continues to undergo, significant evolutions. In the last two decades, new multimodality strategies have been developed. The ability to predict tumor response before treatment could significantly impact the selection of patients for preoperative combined-modality therapy, as well as potentially modify postoperative treatment plans. The present review analyzes the new molecular targets that could be involved in predicting response and prognosis.