Pancreatic adenocarcinoma is a highly lethal disease with anecdotal long-term survivorship when the disease is inoperable at presentation. A new era in the treatment of advanced pancreatic cancer commenced a decade ago with the advent of gemcitabine as a standard of care. While many large phase III trials have been conducted in the last 10 years, it has proved a difficult challenge to advance beyond the modest bar set by gemcitabine. For the most part, gemcitabine-combination cytotoxic studies have been negative where the principal end point has been overall survival with only a few noted exceptions; however, for vigorous individuals with bulky or symptomatic disease, a gemcitabine-based fluoropyrimidine or platinum combination is considered a standard of care and these data are reviewed in detail. In this new era of targeted therapy, the addition of erlotinib to gemcitabine has provided an alternate standard option to single-agent gemcitabine or gemcitabine-based cytotoxic combinations, a topic which will be discussed in a separate chapter. Other phase III studies of gemcitabine and bevacizumab and gemcitabine and cetuximab, respectively, which were both preliminarily reported as negative, have provided an indirect endorsement for the relative value of cytotoxic therapy in advanced pancreatic cancer. This underscores the major therapeutic hurdles that we have to surmount in this most challenging of human malignancies.