Pancreatic cancer is one of the most frequently reported gastrointestinal tumors and has been reported to have a 5-year survival rate of < 5%. It is most commonly diagnosed at an advanced stage and until recently, the most frequently administered treatment for patients with advanced disease has been palliative 5-fluorouracil (5-FU)-based chemotherapy. However, in clinical trials, the novel antinucleoside gemcitabine is currently considered the standard of care and has demonstrated both a survival benefit over 5-FU and an improvement in disease-related symptoms in those patients with advanced disease. The current review presents an overview of recently completed and ongoing clinical trials of gemcitabine/5-FU combination therapy for pancreatic cancer. In these trials, the administration of 5-FU varied widely from bolus injection to 24-hour infusion to protracted infusion over several weeks. These variations make a definitive judgment of this combination difficult, especially because the majority of the data represent only Phase I and Phase II study results. Although a recently completed randomized Phase III trial of gemcitabine plus bolus 5-FU versus gemcitabine failed to show a clinically meaningful survival benefit for the combination arm, current data indicate that other gemcitabine/5-FU combinations might provide a therapeutic advantage over gemcitabine alone. However, the results of ongoing Phase III studies must be reviewed before a definitive statement can be made regarding the value of this combination in the treatment of pancreatic cancer.