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Abstract More than 60 years ago, James Neel proposed the Thrifty Genotype Hypothesis to explain the widespread prevalence of type 2 diabetes in Western, industrial contexts. This hypothesis posits that variants linked to conservative energy usage and increased fat deposition would have been favored throughout human evolution due to the advantages they could provide during periods of resource limitation. However, in industrial environments, these variants instead produce an increased risk of obesity, metabolic syndrome, type 2 diabetes, and related health issues. This hypothesis has been popular and impactful, with thousands of citations, many ongoing debates, and several spin-off theories in biomedicine, evolutionary biology, and anthropology. However, despite great attention, the applicability and utility of the Thrifty Genotype Hypothesis (TGH) to modern human health remains, in our opinion, unresolved. To move research in this area forward, we first discuss the original formulation of the TGH and its critiques. Second, we trace the TGH to updated hypotheses that are currently at the forefront of the evolutionary medicine literature—namely, the Evolutionary Mismatch Hypothesis. Third, we lay out empirical predictions for updated hypotheses and evaluate them against the current literature. Finally, we discuss study designs that could be fruitful for filling current knowledge gaps; here, we focus on partnerships with subsistence-level groups undergoing lifestyle transitions, and we present data from an ongoing study with the Orang Asli of Malaysia to illustrate this point. Overall, we hope this synthesis will guide new empirical research aimed at understanding how the human evolutionary past interacts with our modern environments to influence cardiometabolic health.