Approximately 43,000 new cases of pancreatic ductal adenocarcinoma (PDAC) are identified yearly in the United States. Surgical resection offers the only chance for cure with 5-year survival rates approaching 20%. However, only 80% of patients are candidates for a potentially curative resection because of metastatic disease (50%) or locally advanced tumors (30%). Perhaps more than any other stage of pancreatic cancer, patients with stage III locally advanced or unresectable tumors derive the most benefit from amultidisciplinary team approach. A typical treatment regimen begins with systemic therapy to control micrometastatic disease followed by radiation for local control. At each step of treatment, the surgeon is involved in assessing the resectability. Unfortunately, “downstaging” is estimated to occur in only 10%-15% of patients, and despite multimodality therapy, the median survival remains only 8-12 months. As such, locally advanced pancreatic cancer presents a difficult problem for the multidisciplinary team. Patients with locally advanced, albeit unresectable disease, should theoretically benefit from maximal local therapy. However, currently, there are very few treatment options for aggressive localized therapy in these patients. In highly selected cases, aggressive operations such as pancreatectomy with en bloc resection of the celiac axis can be performed, but these types of operations are only possible in few patients. Until recently, modest improvements in the prognosis and quality of life for locally advanced PDAC have focused on systemic chemotherapy and radiation therapy. Recently, several reports have described the technique and the outcome of ablative techniques for locally advanced PDAC. This article focuses on irreversible electroporation (IRE), which is a novel method for focal tumor ablation in the pancreas. Until recently, locoregional cancer therapies focused on the application of thermal energy for tissue destruction, such as radiofrequency ablation, microwave ablation, and cryoablation. Although effective in other organs such as the liver or kidney, these technologies lack safety and efficacy in the pancreas owing to the risk of thermal damage to adjacent structures and significant thermal dissipation from large adjacent blood vessels. IRE applies short, high-voltage pulses to the tissue to permeabilize cell membranes and induce cellular apoptosis. As IRE relies on apoptosis to induce cell death, structures formed by proteins such as vascular elastin and collagenous structures are not damaged, which should lead to preservation of blood vessel scaffolding. In addition, as IRE is nonthermal, there should be no heat-cold sink effect. Both are