Despite improvements in the treatment of gastrointestinal cancers, 5-year survival rates for advanced-stage patients remain disappointing. Therefore, the need exists to develop innovative new therapies while optimizing the current ones. Pharmacogenetics can be helpful in this context. Metabolism of cancer drugs varies according to age, gender, diet, concurrent use of other drugs, and existing comorbidities, including impaired liver and renal function. In addition, metabolizing enzymes, drug-transport proteins, metabolites, and drug receptors are genetically determined. It has also been demonstrated that genetic mutations within a tumor can be a determining factor with regard to response to treatment. The most common agents used in the treatment of digestive system tumors - 5-fluorouracil, oxaliplatin, cisplatin, irinotecan, gemcitabine, and newly developed biologic agents bevacizumab, cetuximab, panitumumab, and erlotinib-will be reviewed from a pharmacogenetic perspective. The US Food and Drug Administration has approved the UDP-glucuronosyltransferase 1A1 test in patients treated with irinotecan, and additional approval of newer tests is anticipated. Increasing availability of these sophisticated assays is expected to facilitate the delivery of more effective, less toxic chemotherapy regimens in the management of relatively resistant tumors of the gastrointestinal tract.