Pancreatobiliary malignancies are relatively uncommon and the overall prognosis is poor. Treatment options for advanced disease are limited to systemic therapy for metastatic disease and a combination of systemic therapy and radiation therapy for locally advanced but unresectable tumors. There have been significant advances in the treatment of pancreatobiliary cancers in recent years but the prognosis for patient survival remains disappointingly poor. We review the current treatment options for locally advanced pancreatobiliary malignancies and highlight recent advances in systemic therapy, including novel approaches using targeted treatments.