Esophageal cancer is one of the most lethal malignancies. Surgical resection of the tumor from the primary site has been the standard treatment, especially for localized squamous cell carcinoma, but considerable clinical efforts during the last decade have resulted in novel courses of treatment. These options include chemoradiotherapy, consisting of a continuous infusion of 5-fluorouracil (5-FU), cisplatin (CDDP), and concurrent radiation. Given the substantial inter- and/or intra-individual variation in clinical outcome, future improvements will likely require the incorporation of a novel anticancer drug, pharmacokinetically guided administration of CDDP or 5-FU, and identification of potential responders by patient genetic profiling prior to treatment. In this review, the latest information on incidence, risk factors, biomarkers, therapeutic strategies, and the pharmacokinetically guided or genotype-guided administration of CDDP and 5-FU is summarized for future individualization of esophageal cancer treatment.