With a worldwide incidence of more than 200,000 cases and almost as many deaths, pancreatic carcinoma (PC) remains one of the leading causes of cancer deaths, especially in the Western world. Due to the late onset of symptoms, almost all patients suffer from disseminated disease at the time of diagnosis and only a minority will ever be candidates for radical surgery. Only about one tenth of the operated patients remain disease free. For these reasons, development of effective palliative systemic therapy is important. Almost a decade ago, gemcitabine replaced 5-Fu as the gold standard in systemic treatment of advanced PC. Since then, a number of trials have investigated the potential additional effect of several cytotoxic or targeted agents in combination with gemcitabine. As shown in this review, nearly all these trials have proved disappointing. This review provides an overview of the results of current phase III trials of gemcitabine based systemic therapy. Furthermore, we discuss the role of systemic therapy compared to BSC only and the potential future role of targeted therapies.