Only modest progress has been made in improving the overall survival of pancreatic cancer patients during the past 20 years with standard cytotoxic chemotherapy drugs. More work needs to be done to address the key biologic characteristics of pancreatic cancer that make it so aggressive, metastasizing at an early stage, and more refractory to standard treatments than most other solid tumor types. Here, we discuss the emerging role of targeted therapy in pancreatic cancer and the status of currently available and tested agents. We also point out the potential pitfalls in current trial designs and recommend new methods for testing novel compounds in this heterogeneous and difficult-to-treat group of patients.