The standard of care in locally advanced rectal cancer is neoadjuvant chemoradiotherapy (nCRT) followed by radical surgery. However, patients with locally advanced rectal cancer have been shown to present different treatment responses. The utility of clinicopathological and radiological features are limited due to lack of adequate sensitivity and specificity. What's more, although molecular biomarkers have the potential to predict response to nCRT at an early time point, none have currently reached the clinic. Hence, only by integrating diverse types of biomarkers including clinicopathological and imaging features, identification of mechanistic link to tumor biology to develop a sensitive and cost-effective molecular biomarker panel can we predict the response to nCRT accurately. In the present study, we review the recent advance in tissue-and blood-based molecular biomarker research and illustrate their potential in predicting nCRT response in rectal cancer.