Esophageal cancer (EC) is an aggressive malignancy with increasing incidence worldwide. Surgery is still the most effective treatment, however, both the high rate of local and distant recurrences and surgery-related complications led us to investigate new preoperative strategies. In this review, we discuss the role of neoadjuvant therapy for locally advanced EC with a focus on preoperative chemoradiation (trimodality treatment). Furthermore, the last fifteen years of published literature and our experience have been also reviewed. In the preoperative setting, few trials have reported a significant benefit with fluoropyrimidine and platinum compound-based neoadjuvant chemotherapy, compared to surgery alone. A large number of phase III trials and meta-analyses have demonstrated improved outcomes with preoperative chemoradiation vs. neoadjuvant chemotherapy or surgery alone. Therefore, trimodality therapy can be considered the most effective option in the management of locally advanced EC. Addition of drugs targeting VEGF or HER2 to standard chemotherapy appears to be feasible but needs to be explored more accurately. FDG-PET may predict both response to neoadjuvant treatments and prognosis.