Pancreatic cancer is currently the fourth leading cause of cancer-related deaths with a high fatality rate, and is predicted to become the second leading cause of cancer mortality in the United States by 2030. Current 5-year survival of pancreatic cancer patients is only around 10%. Pancreatic cancer exhibits a substantial resistance to therapeutic options, in part due to the dense stromal microenvironment. Cancer immunotherapy has revolutionized the treatment of multiple malignancies, and – along with surgery, radiotherapy, and chemotherapy – has been recognized as the fourth pillar of cancer therapy. The classical checkpoint inhibitors however did not show successful results in pancreatic cancer, due to the immunosuppressive and immune privileged tumor microenvironment, and poor T-cell infiltration. Yet, targeting and reprogramming the tumor microenvironment could switch the immune system toward an anticancer response, and improve sensitivity toward immunotherapy as well as established chemotherapy. In this chapter, we discuss challenges facing pancreatic cancer immunotherapy as well as recent preclinical advances and clinical trials aiming at the development of improved immunotherapy treatment options for pancreatic cancer patients.