In 1962, under the title “Diabetes mellitus: A ‘thrifty’genotype rendered detrimental by ‘progress’?,’’I published the suggestion that the basic defect in diabetes mellitus was a quick insulin trigger.’This was an asset to our tribal, hunter-gatherer ancestors with their intermittent, sometimes feast-or-famine alimentation, since it should have minimized renal loss of precious glucose. Currently, however, it was hypothesized that overalimentation in the technologically advanced nations resulted ininsulin levels that elicited the insulin antagonists popularized by Vallance-Owen and colleagues, resulting in diabetes mellitu~.*-~ The changing dietary patterns of Western civilization had compromised a complex homeostatic mechanism. My paper was written before the clear distinction between type I and type I1 diabetes had been drawn, but in retrospect it was directed at type I1 or non-insulin-dependent diabetes mellitus (NIDDM). This quick insulin trigger was under a (still) poorly-defined genetic control. Since too quick an insulin trigger might be as disadvantageous as one that is too slow, it was suggested that this genetic control might take the form of a balanced polymorphism, by analogy with the polymorphisms for the sickle cell allele (BS) then receiving so much attention. When other laboratories could not confirm Vallance-Owen’s insulin antagonists (except in rare cases), the original physiological basis for the hypothesis collap~ ed.~ Although alternative “balance” hypotheses came to mind, they were neither as simple nor as intellectually sati~ factory.~ However, the problem remained: why is the predisposition to NIDDM so frequent? Explanations based on the “thrifty genotype” hypothesis continue to be in~ oked.~-’~ Over the past 35 years, it has become increasingly clear that essential hypertension and obesity share many of the epidemiological features of NIDDM. Both are diseases of civilization, with a very gradual onset. Both are familial, with the disease the result of a complex interplay of genetic and environmental factors. This essay will compare and contrast current facts concerning the genetic bases for all three dis-