Since the 1940s, numerous cases of non-insulin-dependent diabetes mellitus (NIDDM) have been observed in certain American Indian populations. Extremely high prevalence rates of NIDDM occur most strikingly in several tribes of Paleo-Indians, whose ancestors migrated to North America greater than 11,000 yr ago. Archaeological evidence from that period indicates that certain groups of Paleo-Indians maintained an arctic-like hunter-gatherer life-style in an area in temperate North America ranging from Wyoming to Arizona. This life-style featured a reliance on unpredictable big game species as a major food source. However, at this time, big game species were becoming extinct. It is hypothesized that those Paleo-Indians who relied on big game as a food source developed a "thrifty" genotype that allowed a selective advantage during the periods of fasting that occurred between big game kills. It also is hypothesized that this thrifty genotype in these Indians may contribute to NIDDM when a sedentary life-style is adopted and food sources are constant. Because insulin resistance in muscle is a major feature of NIDDM, it is possible that insulin resistance per se is the phenotypic expression of the thrifty genotype.