Almost 30% of patients with pancreatic cancer present with large, locally advanced tumors in the absence of distant metastases. Because surgical resection is frequently contraindicated by vascular invasion, locally advanced pancreatic cancer has a dismal prognosis with a 6-10-month median survival. Recent advances in the multimodality treatment of other gastrointestinal malignancies have not altered the management of patients with locally advanced pancreatic cancer, a clinical dilemma reflected by the number of nonrandomized trials and anecdotal reports addressing this difficult disease. Our review summarizes the current status of aggressive surgical resection and neoadjuvant chemoradiation for locally advanced pancreatic cancer and suggests a treatment algorithm for patients with this disease based upon published clinical evidence.