Early interventions to prevent type 2 diabetes mellitus (T2DM) demand a better understanding of its underlying mechanisms. Nonobese healthy subjects with a strong family history of T2DM (FH⁺ subjects) hold a key to this end by allowing the study of the disease before the development of confounding factors, such as obesity or hyperglycemia. In this article, we share our experience over the past decade in studying FH⁺ subjects and how lipotoxicity alters glucose metabolism in such individuals, in particular pancreatic β-cell function. FH⁺ subjects have no obvious clinical abnormalities, but when carefully studied, reveal severe hepatic/muscle/adipose tissue insulin resistance and subtle defects in β-cell function. In most subjects, metabolic adaption allows freedom from diabetes for decades. However, the obesity epidemic is drastically changing this. Given the unique susceptibility of pancreatic β cells to free fatty acids in FH⁺ subjects, interventions that protect against obesity-induced lipotoxicity may hold the greatest promise for preventing T2DM in genetically predisposed individuals.