Pancreatic cancer is a particularly challenging malignancy, given its usually advanced stage at diagnosis and its rather limited treatment options. Gemcitabine has been standard therapy for advanced pancreatic cancer for well over a decade. The addition of capecitabine or erlotinib to gemcitabine has resulted in modestly improved, although still poor, overall survival. The majority of the recently completed randomized trials, however, have failed to demonstate an improvement of newer treatments over single-agent gemcitabine. Efforts currently underway center on new cytotoxic chemotherapy drugs, as well as novel targeted agents inhibiting various molecular pathways. Newly discovered proteins and cellular elements involved in tumor growth and invasion are potential therapeutic targets, and have become the focus of current trials, as well as future clinical trials. A better understanding of the biology of the disease at the basic science level, and epidemiology and risk factors from a public-health perspective, are needed. Continued research is clearly warranted with the goal of improving survival and optimizing treatment outcomes in locally advanced and metastatic pancreatic cancer.