In subgroups of gastric cancer patients, chemotherapy treatments carry a high risk of toxicity without any clear evidence of antitumor activity. Individualization of therapy is required to treat each patient with the optimal drug and dose. Genetic polymorphisms are the hereditary determinants for interindividual variations of drug effect and the genetic approach represents a new tool to design a tailored therapy. This review focuses on the relevance of the host polymorphisms involved in metabolism, cellular transport and interaction with molecular targets of the drugs used in gastric cancer in conventional or innovative chemotherapy regimens. Pharmacogenetic studies based on a single gene or multi-gene approach (pharmacogenomics) are promising to identify gastric cancer patients at risk for adverse toxicity, but larger and controlled studies are needed to justify changes in the chemotherapeutic strategies.