Even though pancreatic cancer accounts for only 2% of all cancer diagnoses in the U.S., it is the fourth-leading cause of cancer death and one of the most difficult malignancies to manage. Because of the usually late onset of symptoms, only 10%-15% of patients present with resectable disease, whereas the remaining 85%-90% present with locally advanced unresectable or metastatic disease. Despite a lack of consistent evidence from previous clinical trials, chemotherapy in addition to radiation therapy is the most commonly used approach in treating locally advanced pancreatic cancer. The most appropriate chemotherapy in combination with radiation is still debatable between 5-fluorouracil and gemcitabine, and novel trends to prevent resistance and enhance efficacy incorporate biologically targeted agents. This paper reviews the current management options, controversies, and ongoing and future directions for the treatment of locally advanced adenocarcinoma of the pancreas.