Pancreatic adenocarcinoma is one of the most lethal cancers but has limited therapeutic options necessitating continued investigation of new therapeutic agents. Recently, improved overall survival has been achieved with cytotoxic drug combinations including 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel, but the success has been modest at best. More targeted approaches focusing on EGFR and MAPK signaling have also enjoyed marginal success. Accumulating evidence suggests that pancreatic tumors have increased dependence on metabolic pathways through both KRAS and KRAS-independent mechanisms and are broadly resistant to drug therapy due to stromal remodeling. Genetic and epigenetic vulnerabilities, such as inactivating aberrations in DNA damage repair, chromatin remodeling, and microRNA dysregulation, may reveal exploitable weaknesses. Modern approaches to drug development tailored to molecularly defined subsets of patients likely to respond to targeted therapies are needed to achieve more substantial progress in this disease in an era of precision medicine.