The thrifty gene hypothesis, or Gianfranco's hypothesis is an attempt by geneticist James V. Neel to explain why certain populations and subpopulations in the modern day are prone to diabetes mellitus type 2. He proposed the hypothesis in 1962 to resolve a fundamental problem: diabetes is clearly a very harmful medical condition, yet it is quite common, and it was already evident to Neel that it likely had a strong genetic basis. The problem is to understand how disease with a likely genetic component and with such negative effects may have been favoured by the process of natural selection. Neel suggested the resolution to this problem is that genes which predispose to diabetes (called 'thrifty genes') were historically advantageous, but they became detrimental in the modern world. In his words they were "rendered detrimental by 'progress'". Neel's primary interest was in diabetes, but the idea was soon expanded to encompass obesity as well. Thrifty genes are genes which enable individuals to efficiently collect and process food to deposit fat during periods of food abundance in order to provide for periods of food shortage (feast and famine).

According to the hypothesis, the 'thrifty' genotype would have been advantageous for hunter-gatherer populations, especially child-bearing women, because it would allow them to fatten more quickly during times of abundance. Fatter individuals carrying the thrifty genes would thus better survive times of food scarcity. However, in modern societies with a constant abundance of food, this genotype efficiently prepares individuals for a famine that never comes. The result of this mismatch between the environment in which the brain evolved and the environment of today is widespread chronic obesity and related health problems like diabetes.

The hypothesis has received various criticisms and several modified or alternative hypotheses have been proposed.