To review the use of gemcitabine-based therapy in pancreatic cancer, including fixed-dose-rate (FDR) infusion and novel combinations. On the basis of pharmacokinetic data, studies have been performed using an FDR of gemcitabine of 10 mg/m(2)/min in an effort to maintain a critical plasma concentration of gemcitabine, and thus increase tumor cytotoxicity and therapeutic efficacy. The dose-limiting toxicities in Phase I studies were mucositis and myelosuppression. A multicenter Phase II study compared two schedules of gemcitabine in patients with pancreatic cancer, a single dose of 2200 mg/m(2) infused for 30 min, and a constant infusion of 1500 mg/m(2) given at 10 mg/m(2)/min. A somewhat improved response rate and survival for the FDR arm compared with the 30-min-infusion arm was observed. In addition, a wide variety of new compounds targeting specific molecules involved in cell control, cell growth, and apoptosis have been used in combination with gemcitabine and are reviewed. Further development of FDR gemcitabine in combination with other chemotherapeutic agents is ongoing. Because none of the new compounds investigated has as yet shown improvement compared with single-agent gemcitabine in prospectively randomized trials, gemcitabine remains the standard of care in pancreatic cancer.