Non-insulin-dependent diabetes mellitus (NIDDM) is an important health problem in the black population of southern Africa. Whether the primary cause of NIDDM is insulin secretory dysfunction or peripheral insulin resistance is unknown. In westernised populations it is believed that insulin resistance and hyperinsulinaemia occur in the early stages of disease, followed later by progressive impairment of insulin secretion. However, we suggest that in the southern African black population a decrease in the mass of functioning beta cells is an important event, making these people vulnerable to the deleterious effects of insulin resistance induced by obesity and other factors. These abnormalities are, in turn, associated with insulin receptor down-regulation. An accelerated decline in beta-cell function then follows in susceptible individuals, ultimately producing striking insulinopenia. Insulinopenic NIDDM in black southern Africans may partly explain why this population has a comparatively low incidence of macrovascular complications and also predicts a short-lived therapeutic response to oral sulphonylureas in most patients.