Systemic chemotherapy with single-agent gemcitabine or a gemcitabine-based regimen still remains a standard of care for the treatment of patients with locally advanced and metastatic pancreatic cancer. To date, no standard treatment approach for patients that show progressive disease during gemcitabine therapy is defined. Several clinical trials have evaluated the safety and efficacy of second-line chemotherapy after gemcitabine failure in this patient population. Based on the currently available data, there is increasing evidence that selected patients may derive clinical benefit from salvage chemotherapy, also with regard to survival. However, results from large randomized Phase III trials are still lacking and therefore no evidence-based treatment recommendation can be given for patients with advanced pancreatic cancer after failure of first-line gemcitabine.