Since 1997, when gemcitabine showed superior clinical benefit to single-agent 5-fluorouracil, it has remained the standard of care for the treatment of advanced pancreatic cancer. Numerous new agents, both cytotoxic and targeted, have been tested against this standard. Some trials showed improved response rates or progression free survival, but there was no clear improvement in survival. For the current report, those trial results were reviewed in depth for methodology, endpoints, and study characteristics. More recent studies have shown progress. Studies with combinations of gemcitabine and capecitabine and with the epidermal growth factor receptor antagoinist, erlotinib, have demonstrated survival benefits. Currently, studies of combinations with oxaliplatin, bevacizumab, and cetuximab are ongoing. Other targeted therapies also are considered for future clinical trials. Based on a comprehensive review of past trials, a consensus on endpoints in the treatment of pancreatic cancer and an approach to new trials is presented.