The current oncology practice of treating cancer with aggressive doses of radiation and chemotherapy is potentially disastrous, as response and side effects vary depending on several factors including pharmacogenetics. This study is the first to evaluate esophageal cancer treatment with a pharmacogenetic paradigm and its application of pharmacogenetic analysis to multiple genes in each drug action pathway as a means of developing a more accurate and consistent risk prediction model. This study has enrolled 235 patients with resectable adenocarcinoma or squamous cell carcinoma of the esophagus who had been treated with chemoradiation followed by esophagectomy. The preliminary finding that methylenetetrahydrofolate reductase polymorphisms modify 5-fluorouracil response supports the hypothesis that response or resistance to therapy in esophageal cancer patients may be modulated by genetic variants involved in the metabolism or mechanism of chemotherapy drug action. Our ongoing esophageal cancer research aims to determine individual pharmacogenetic profiles to identify patients most likely to have chemotherapeutic benefit and patients with the highest risk of suffering genotoxic side effects. These profiles will ideally lead to individualized therapies, improved treatment outcomes, and a movement toward clinically applied pharmacogenetics. This emergent area of biomedicine could lead to substantially improved clinical outcomes for patients with adenocarcinoma or squamous cell carcinoma of the esophagus.