In the last few years the knowledge of molecular oncology has led to the development of many new biological agents whose targets are extracellular or intracellular molecules involved in the main signalling pathways that play major roles in cancer development. These agents represent a new approach to gastrointestinal malignancies, as for many other types of tumors; preliminary data show that targeted therapy may enhance activity of chemotherapeutic agents (i.e. cetuximab in metastatic colorectal cancer (CRC)) or be active as monotherapy (i.e. imatinib in gastro-intestinal stromal tumors). Despite the encouraging preclinical results, the majority of these compounds have not yet produced convincing clinical results. However, these new agents raise a new challenge in the treatment of gastrointestinal cancers, especially for CRC.