Surgical resection is the only curative option for patients with gastrointestinal carcinomas. Unfortunately, the majority of patients are diagnosed in advanced stages when surgery is not possible. Moreover, the incidence and mortality for certain type of tumors such as hepatocellular carcinoma or pancreatic cancer are steadily increasing worldwide. In spite of the advances in the development of molecular targeted therapies for cancer, the impact on patient survival has been rather limited. It is unlikely that individual agents would be ultimately successful as monotherapy. There is a growing area of research focused on the combination of classical chemotherapy (e.g. cyclophosphamide, gemcitabine, paclitaxel and doxorubicin) with radiotherapy and/or gene therapy strategies. Combined approaches seem to be required due to multiple resistance mechanisms that tumors utilize to limit the activity of chemotherapeutic agents (e.g. the occurrence of multidrug resistance or epigenetic alterations), evade immune responses (e.g. induction of regulatory T cells or myeloid-derived suppressor cells) and to generate resistance against anti-angiogenesis or to radiotherapy by, for example, the induction of hypoxia-inducible factor 1. In addition, new studies suggest that combination of low dose of conventional chemotherapy and gene therapy could allow the development of synergic mechanisms able to achieve significant therapeutic effects against diverse tumors. Although cancer gene therapy is not yet available in clinical practice, advances being recently made look promising, especially when it was applied in combination with standard chemo- or radiotherapy protocols.