Trimodality based on neoadjuvant chemoradiotherapy (nCRT) followed by surgery is gaining popularity as a treatment strategy for locally advanced esophageal cancer. In this review, we summarize the role of nCRT and the recommended nCRT regimens based on clinical trials and meta-analyses. We analyze the relationship of nCRT with pathologic complete response (pCR) and then identify potential predictive markers of response. Compared with surgery alone and neoadjuvant chemotherapy followed by surgery, trimodality provides longer survival and has the advantage of local control compared with definitive chemoradiotherapy. The standard regimen is a platinum-based regimen with a radiation dose range of 41.4-50.4 Gy by conventional fractionation. Evidence shows that patients with pCR tend to live longer than non-responders, indicating that pCR is a significant prognostic factor for patients with esophageal cancer. Individualized medicine requires predictive markers of individual patients based on their own genes. Currently, no definite marker is proved to be sufficiently sensitive and specific for use in clinical practice, although 18-fluorodeoxyglucose positron emission tomography shows promise in predicting response to nCRT.