Treatment of pancreatic cancer remains challenging today and mostly palliative. Despite many efforts to understand the underlying mechanisms of this aggressive tumoral phenotype and to develop new therapeutic agents, advances in its management and survival benefit are poor. Although gemcitabine remains the backbone of routine therapy in advanced disease, newer drugs, mainly constituted by (multi)targeted agents, represent promising therapeutic areas. In this setting, anti-EGF receptor, antiangiogenic or both therapies combined appear to have valuable potential, providing their optimal and comprehensive development and use in pancreatic cancer. Multitargeted agents, such as receptor tyrosine kinase inhibitor small molecules, combining different therapeutic interventions, also deserve new preclinical and clinical development, supported and paralleled by a translational approach. Over the next few years, we need to identify new target mechanisms in pancreatic carcinogenesis, to rapidly test selected drugs against these targets and imperatively to understand and determine which patients respond and who will benefit from such therapies. Significant advances should be immediately evaluated in the perioperative setting in order to improve the curative approach of this devastating disease.