Gastrointestinal cancers account for a large amount of human tumors. Surgery is the standard treatment for localized gastrointestinal cancer, but in a large number of patients, tumors are unresectable at time of diagnosis and even when resectable, survival is often poor. Current attempts to improve these results include the use of chemotherapy in the adjuvant setting, in the advanced disease, or as neoadjuvant treatment. However, less than half the patients respond to chemotherapeutic treatments, mostly reporting important side-effects. The identification of molecular markers, such as p53, thymidylate synthase, K-ras, and others, may provide an important tool for medical oncologists in defining subsets of patients with gastrointestinal cancers more suitable to benefit from chemotherapy or from experimental therapies. The relationship between the clinical outcome to anticancer drugs and molecular markers in gastrointestinal tumors has been reviewed. Available data are promising, but most of them arise from retrospective and small studies. Well designed, prospective trials are warranted to change the target approach from a general to an individual treatment strategy.