Pancreatic cancer remains one of the most difficult cancers to treat; very few effective therapies are available, with surgery being the sole chance for cure-yet surgery is not a viable option for most pancreatic cancer patients. Immunotherapy has the potential to provide a non-cross-resistant mechanism of antitumor activity that can be integrated with surgery, radiation therapy, and chemotherapy. However, the inherent instability of the tumorgenome as well as tumor tolerance mechanisms are significant practical obstacles that must be overcome if immune-based approaches for pancreatic cancer can achieve its promise. Recent advances in both tumor immunology and vaccine design have already resulted in promising preliminary data from phase I studies, and additional trials are already in progress. This article summarizes some of the progress and challenges in immunotherapy research.