Recently, we have seen major advances in the chemotherapy of gastrointestinal tumors, in particular colorectal cancer, leading to a substantial increase in overall survival of the patients. However, clinical efficacy and also toxicity of a given chemotherapy are still largely unpredictable for the individual patient. Amongst other variables, genetic polymorphisms determine the interindividual heterogeneity in both toxicity and therapeutic efficacy. In this review we present current evidence on host genetic polymorphisms that affect the toxicity or efficacy of three drugs commonly used for the treatment of gastrointestinal malignancies, 5-fluorouracil, irinotecan and oxaliplatin.