Unresectable pancreatic cancer has a dismal prognosis with a median survival of 3-5 months in untreated disease. Since the introduction of gemcitabine, pancreatic cancer may no longer be regarded a chemotherapy-resistant tumor. Treatment with single-agent gemcitabine achieved clinical benefit and symptoms improvement in 20-30% of patients. While 1-year survival was observed in 2% of 5-fluorouracil (5-FU)-treated patients, it was raised to 18% by single-agent gemcitabine. Good treatment tolerability and low incidence of side effects are clear advantages of single-agent gemcitabine. Improvement of efficacy is, however, expected from combination treatment. Gemcitabine and cisplatin given as first-line treatment in three studies achieved a median survival of 7.4-8.3 months. One-year survival was raised to 28% as reported in one study. Comparable activity was obtained by a combination of gemcitabine with 5-FU. Nine studies using gemcitabine in combination with standard-dose or high-dose 5-FU reported a median survival ranging from 5.5 to 13 months. Notwithstanding these promising results, recommendations regarding palliative chemotherapy of pancreatic cancer remain tentative and still need confirmation by presently ongoing phase III trials. Inclusion of pancreatic cancer patients into clinical trials should be a major goal. Outside clinical trials, patients should present with an adequate PS (Karnofsky-performance index greater than or equal to 70) to qualify for chemotherapy. Copyright (C) 2001 S. Karger AG, Basel.