A comparative study of the endocrine pancreas was carried out in genetically diabetic (db) mice and in mice with streptozotocin-induced (Sz) diabetes over a 12-week period of pronounced diabetes. Mice were examined at 9, 12 and 21 weeks of age. Plasma and pancreatic levels of immunoreactive insulin and immunoreactive glucagon were measured in both experimental animal models, and the biochemical data obtained were correlated with ultrastructural observations on the endocrine pancreas. Both pancreatic and plasma immunoreactive insulin levels were severely depressed in all Sz mice. Although pancreatic immunoreactive insulin concentrations in db mice were consistently lower than control values, these animals displayed a hyperinsulinemia which gradually dropped to control levels by 21 weeks. Pancreatic immunoreactive glucagon levels in 12- and 21-week-old db mice were markedly lower than those found in either control or in Sz mice. However, both db and Sz mice in all age groups exhibited a marked and persistent hyperglucagonemia. Pancreatic islet tissue was examined concurrently in control and experimental animals. The ultrastructural changes occurring in the endocrine cells are reported and discussed with regard to the pancreatic and plasma levels of the hormones presently monitored and in light of other recent studies on these animal models.