A new congenic strain of obese mice, C57BK/KsJ-ob, has been developed for comparison with the C57BL/6J-ob congenic strain. While obese mice of both strains are characterized by obesity, hyperphagia, and hyperglycemia, the C57BL/Ks obese mice have severe diabetes, marked hyperglycemia, temporarily elevated plasma insulin concentrations, and typical degenerative changes in the islets of Langerhans. In contrast, the C57BL/6J obese mice have mild hyperglycemia and marked hyperinsulinemia coupled with hypertrophy and hyperplasia of the islets of Langerhans. The severe diabetic condition produced by obese (ob) on the C57BL/KsJ background is similar, if not identical, to that produced by the diabetes (db) gene on the same background. The metabolic disorder produced by these mutations is associated with the capacity of the islets to respond to an increased demand for insulin. The islet response, whether atrophy or hypertrophy, appears to be due to the interaction of the obese and diabetes genes with modifiers in the genetic background rather than the specific consequences of the particular gene. The markedly different diabetic syndromes that result when the obese mutation is on different genetic backgrounds emphasize the importance of strict genetic control in studies with obese-hyperglycemic mutants.