Patients with multiple endocrine neoplasia 1 (MEN1) syndrome have a germline mutation in the MEN1 gene. Loss of the wild-type allele can initiate endocrine tumorigenesis. Microscopic and macroscopic pituitary, parathyroid, and pancreatic tumors (referred to as the 3 P's) show loss of the wild-type MEN1 allele up to 100%. In contrast, the duodenal gastrinoma pathogenesis in MEN1 syndrome follows a hyperplasia-to-neoplasia sequence. Gastrinomas have loss of heterozygosity of the MEN1 locus in <50%, and invariably coincide with linear, diffuse, or micronodular gastrin-cell hyperplasia. The factor initiating the gastrin-cell hyperplasia-to-neoplasia sequence is unknown. In this perspective, we argue that hypercalcemia may promote the gastrin-cell hyperplasia-to-neoplasia sequence through the calcium sensing receptor. Hypercalcemia is present in almost all patients with MEN1 syndrome due to parathyroid adenomas. We propose a parathyroid-gut axis, which could well explain why patients with MEN1 syndrome are regularly cured of duodenal gastrinoma after parathyroid surgery, and might cause MEN1 syndrome phenocopies in MEN1-mutation negative individuals with parathyroid adenomas. This perspective on the pathogenesis of the gastrin-cell hyperplasia and neoplasia sequence sheds new light on tumorigenic mechanisms in neuroendocrine tumors and might open up novel areas of gastrinoma research. It may also shift focus in the treatment of MEN1 syndrome-related gastrinoma to biochemical prevention.