Little progress has been made on the treatment of advanced pancreatic cancer. Gemcitabine has been an acceptable standard for more than a decade. The benefit of single-agent gemcitabine in advanced and metastatic pancreatic cancer is small. Adding other chemotherapy agents to gemcitabine has not resulted in meaningful improvement in survival. The randomized trials studying the addition of molecular targeting agents (cetuximab, bevacizumab, farnesyl transferase inhibitors and metalloproteinase inhibitors) to gemcitabine compared with gemcitabine alone have been disappointing. A small gain in median survival by adding erlotinib to gemcitabine has recently been reported. We herein review novel agents in pancreatic cancer that may change the current nihilistic approach in the management of this challenging disease.