Gastrointestinal (GI) tumors are a leading cause of cancer-related deaths in the world. In fact, gastric cancer (GC) is the third cause of cancer deaths, whereas aesophageal neoplasm is the eighth most common cancer worldwide and its incidence, especially adenocarcinoma type, is continuously increasing. Also Hepatocellular carcinoma, Cholangiocarcinoma and pancreatic cancer represent a very interesting model to multidisciplinary approach and recently new drugs are used in their treatment. Currently, new clinical trials are designed including classic chemotherapy in association with either small molecule inhibitors (i.e. Tyrosine Kinase inhibitors) and/or monoclonal antibody (i.e. anti-EGFR antibody). Moreover, a comphrensive list of new molecules for target therapy is included in this issue. The development of new treatment modalities (multidisciplinary approach) and targeted therapy approaches, have contributed to improve the outcome in these cancer diseases. Our expanding knowledge of the molecular biology of malignancy, the related identification of therapeutically-important targets, and the subsequent development of systemic agents that inhibit critical kinases and pathways, have all contributed to great excitement and progress in cancer treatment.