In normoglycemic offspring of two type 2 diabetic parents, low insulin sensitivity (S_I) and low insulin-independent glucose effectiveness (S_G) predict the development of diabetes one to two decades later. To determine whether low S_I, low S_G, or low acute insulin response to glucose are predictive of diabetes in a population at low genetic risk for disease, 181 normoglycemic individuals with no family history of diabetes (FH−) and 150 normoglycemic offspring of two type 2 diabetic parents (FH+) underwent i.v. glucose tolerance testing (IVGTT) between the years 1964–82. During 25 ± 6 years follow-up, comprising 2,758 person years, the FH− cohort (54 ± 9 years) had an age-adjusted incidence rate of type 2 diabetes of 1.8 per 1,000 person years, similar to that in other population-based studies, but significantly lower than 16.7 for the FH+ cohort. Even when the two study populations were subdivided by initial values of S_I and S_G derived from IVGTT's performed at study entry, there was a 10- to 20-fold difference in age-adjusted incidence rates for diabetes in the FH− vs. FH+ individuals with low S_I and low S_G. The acute insulin response to glucose was not predictive of the development of diabetes when considered independently or when assessed as a function of S_I, i.e., the glucose disposition index. These data demonstrate that low glucose disposal rates are robustly associated with the development of diabetes in the FH+ individuals, but insulin resistance per se is not sufficient for the development of diabetes in individuals without family history of disease and strongly suggest a familial factor, not detectable in our current measures of the dynamic responses of glucose or insulin to an IVGTT is an important risk factor for type 2 diabetes. Low S_I and low S_G , both measures of glucose disposal, interact with this putative familial factor to result in a high risk of type 2 diabetes in the FH+ individuals, but not in the FH− individuals.