Pancreatic cancer is one of the world's most lethal diseases. With no effective treatment currently available, there is an urgent need to develop novel therapies. There has been interest in using TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) as an anti-cancer agent, however, studies have demonstrated that the majority of pancreatic cancer cells are resistant to TRAIL, posing a major obstacle in the development of TRAIL as a therapeutic agent. In our recent work with tumor cell lines, we have discovered that modulating certain TRAIL-resistant genes including cFLIP or RIP with siRNA will sensitize pancreatic cancer cells to TRAIL treatment. This therapeutic strategy has the potential to provide an effective treatment regimen for a devastating disease.