Many of our most onerous health burdens today are driven by complex and poorly understood interactions between a person’s genetic makeup and their environment. In other words, genetic variation may predispose individuals toward physiological sensitivity or resilience in the face of environmental perturbations. Our modern environments are deeply diverged from the ancestral selective pressures that have shaped human genetic variation through evolutionary time, raising the question of how much the “mismatch” between our genomes and modern life is responsible for the non-communicable diseases that plague modern societies. This concept, known as the evolutionary mismatch hypothesis, has become a central tenet of evolutionary medicine, however, this hypothesis has been difficult to robustly test in practice. At the genetic level, this hypothesis predicts that loci with a history of selection will exhibit “genotype by environment” (GxE) interactions, with different phenotypic effects in “ancestral” versus “modern” environments. Our work leverages this hypothesis, in combination with the development of high-throughput approaches, to advance our understanding of how and why some individuals are more sensitive to environmental stressors than others and identify the molecular and genetic drivers of this variation.