Forty human insulin-producing tumors were investigated with histochemical, immunohistological and ultrastructural methods and extracted for insulin and proinsulin. These studies resulted in the following findings: 1) A variable number of tumor cells contained only a few or often no beta granules. 2) The insulin concentration was lower and the proinsulin percentage higher in insulinoma cells compared with normal beta-cells. 3) According to the ultrastructural appearance of the secretory granules four types of insulinoma were established. 4) Insulinomas frequently contained cells with atypical secretory granules which were Grimelius silver-positive. Their similarity to the Type IV islet cell and to cells regularly found in gastrinomas, Verner-Morrison tumors and glucagonomas suggests that all endocrine pancreatic tumors originate from a common precursor cell. 5) The morphological and biochemical findings support the theory that uncontrolled hormone release and/or decreased storage capacity are responsible for fasting hyperinsulinism in insulinoma patients. 6) The severity of hypoglycemia symptoms and the result of stimulatory tests were not related to the size, the insulin concentration and the total insulin content of the tumor.