Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate and is notoriously refractory to multiple cancer treatments. In recent years, cancer therapy has expanded beyond traditional cytotoxic chemotherapy to targeted agents and immunotherapy which have been successfully implemented in many cancers. Despite robust pre-clinical research, these novel therapies have only had a small impact on PDAC. However, there have been successes with emerging clinical data supporting a potential role for checkpoint inhibitor therapy and targeted therapy with poly (ADP-ribose) polymerase inhibitors for select subsets of PDAC patients. In this clinical review, we discuss recent pre-clinical evidence for targeting metabolic pathways as well as prevalent intratumoral immune subsets, and focus on clinical trials designed to test novel agents in PDAC. The challenge of translating pre-clinical findings to patients remains substantial and many clinical trials yield negative results, but collaborative efforts and renewed focus on novel clinical trials have led to optimism that we will identify additional options for PDAC patients and change outcomes for this deadly disease.“,”Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate and is notoriously refractory to multiple cancer treatments. In recent years, cancer therapy has expanded beyond traditional cytotoxic chemotherapy to targeted agents and immunotherapy which have been successfully implemented in many cancers. Despite robust pre-clinical research, these novel therapies have only had a small impact on PDAC. However, there have been successes with emerging clinical data supporting a potential role for checkpoint inhibitor therapy and targeted therapy with poly (ADP-ribose) polymerase inhibitors for select subsets of PDAC patients. In this clinical review, we discuss recent pre-clinical evidence for targeting metabolic pathways as well as prevalent intratumoral immune subsets, and focus on clinical trials designed to test novel agents in PDAC. The challenge of translating pre-clinical findings to patients remains substantial and many clinical trials yield negative results, but collaborative efforts and renewed focus on novel clinical trials have led to optimism that we will identify additional options for PDAC patients and change outcomes for this deadly disease.