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Majority of the patients with pancreatic cancer present with advanced disease that is lethal and notoriously difficult to treat. Survival has not improved dramatically despite routine use of chemotherapy and radiotherapy; this situation signifies an urgent need for novel therapeutic approaches. The treatment of advanced disease with gemcitabine has only a modest activity on survival with a favorable impact on quality of life. So far, the current targeted agents that have been used in combination with gemcitabine have failed to improve clinical outcomes. This failure may stem from the heterogeneous molecular pathogenesis of pancreatic cancers, which involves several oncogenic pathways and defined genetic mutations. 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. Pancreatic cancer remains the 4th leading cause of cancer death in the U.S.A.. How to treat a non-resectable pancreatic cancer has been a challenging topic for all medical oncologists. Historical 5- fluorouracil has been replaced by single agent gemcitabine since 1997. Numerous combinations using gemcitabine as a backbone have been tested in clinical trials; unfortunately, none of the combinations including the ones with biological agents was proved to be significantly superior to gemcitabine alone. This year, more combinations were investigated and the results were presented on the meeting. In first-line setting, two large phase III trials (Abstracts #4504 and #4601) failed to prove any additional benefit of a second cytotoxic agent or a vaccine. Folinic acid plus 5-FU plus oxaliplatin (FOLFOX) and 5-fluorouracil plus leucovorin plus irinotecan (FOLFIRI) could be considered in the second-line setting after failure of gemcitabine therapy (Abstract #4618). Novel agents (Abstracts #4501, #4625, #4626, #4617) provide some hope; however, in general, all combinations are still significantly relying on the backbone of gemcitabine. Thinking beyond the gemcitabine box and exploring novel agents are very crucial now.