Advanced pancreatic adenocarcinoma historically has a poor prognosis and the mortality rate has remained unchanged for over a decade. Common treatment options for patients with advanced pancreatic cancer include chemoradiation and/or chemotherapy. Single-agent gemcitabine has been considered the standard of care since 1997. Recently published findings indicate that the oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) treatment regimen significantly improves overall survival compared with gemcitabine. Research has shifted to focus on understanding the causes the resistance of pancreatic cancer to chemotherapy and potential methods to overcome it. This review will focus on the current treatment options, the evolution of targeted therapy, novel agents on the horizon and potential options to ameliorate chemoresistance.