Chemo(radio)therapy is becoming the new standard for patients with locally advanced pancreatic cancer. In case of tumor regression on imaging, surgical resection can be undertaken, albeit often with the need for extended procedures. Reevaluation of the current routine pathology procedures is required to establish the appropriate histopathological approach of the resulting specimens. This review focusses on margin status, which is universally considered a core data item of the pathology report, of relevance to both the management of the individual patient and the evaluation of the result of surgery in this particular patient group. As explained in this review, due to the cytoreductive effect of neoadjuvant therapy, the conventional definition of a tumor-free margin ("R0") based on 1 mm clearance is not adequate. Furthermore, the complexity of many of the specimens following extended or multivisceral surgical resection make margin assessment challenging. These large specimens require extensive sampling, which is not always easily implemented in daily practice. At present, there is marked divergence in pathology practice, and consequently, neither the true R0-rate nor the exact prognostic effect of the margin status have been definitively established for resected locally advanced pancreatic cancer. A concerted effort towards uniform and optimal margin assessment is unfortunately still lacking.