Pancreatic adenocarcinoma is a leading cause of cancer death in western countries. The treatment of advanced disease with gemcitabine has only a modest activity on survival with a favourable impact on quality of life. However, recent data support the evidence that the combination of gemcitabine with erlotinib, capecitabine or platinum compounds could be more active than gemcitabine alone in advanced pancreatic cancer. New therapeutic strategies, particularly using molecular target agents, are under evaluation. A number of molecular mechanisms responsible of transformation and progression of pancreatic cancer have been identified, opening the possibility to identify also possible pharmacological targets. A promising approach is the pharmacological inhibition of tumor angiogenesis with anti-vascular endothelial growth factor (VEGF) agents, such as bevacizumab, cyclooxygenase-2 inhibitors (celecoxib), thalidomide and others. Also epidermal growth factor receptor (EGFR) plays an important role in progression of pancreatic cancer. Erlotinib, an oral available anti-EGFR compound, was the first agent capable to significantly improve overall survival in a phase III trial, leading to its approval by Food and Drug Administration (FDA) in combination with gemcitabine as first-line therapy. Ongoing studies are exploring the role of targeted therapy in the adjuvant setting. However, despite these promising results, several questions remain to be resolved, including the rational selection of the patients who are more likely to obtain benefit of target therapy, the choice of the optimal therapeutic schedule of therapy, the clinical setting of choice, and the management of the toxicity.