In the last 10 years, there have been a number of major advances that have markedly changed the management of patients with Zollinger-Ellison syndrome. These advances have been described recently in a number of excellent reviews. After reading each of these reviews, including our own, one is left generally with the impression that most of the important problems and particularly those involving surgery in the treatment of this disease have been resolved; however, in considering the possible problems to address in protocols in the coming years in our patients with Zollinger-Ellison syndrome followed at the National Institutes of Health, it became apparent to us that not only will surgery play an increasingly important role in the management of this disease, but that there are a number of major questions in which various aspects involving surgery are not resolved. Furthermore, resolution of a number of these areas will have applicability to the surgical treatment of other islet cell tumors. The purpose of this article is to call attention to these questions with the hope that other investigators may also consider these and specifically attempt to address some of these issues in the surgical treatment of Zollinger-Ellison syndrome in prospective studies.