Inorganic arsenic is a very potent toxicant and of major health concern for millions of people worldwide that are exposed to arsenic through drinking water and food. We recently identified a dramatic increase of specific genetic variants associated with a less toxic arsenic metabolism in a population in the Argentinean Andes, exposed to arsenic in water over thousands of years. This discovery of arsenic tolerance stands as the first documented case of natural selection in humans for a defense against a toxic chemical. The purpose of the project is to elucidate the evolution and molecular mechanisms behind this human adaptation. We first investigate whether other populations exposed to arsenic for a prolonged period show similar genetic adaption. This is performed in a new cohort of women in Bolivia where we characterize arsenic exposure and metabolism using mass spectrometry, arsenic-related health effects by early markers of toxicity, and genetic selection by GWAS and a selection scan. Based on the Argentinean and Bolivian cohorts, we then aim by targeted NGS and biochemical analysis to identify and characterize functional genetic variants that drive arsenic tolerance. This new knowledge helps us understand the past, how humans adapted to environmental toxicants as they settled around the world. Moreover, as most countries have areas where people are exposed to arsenic, knowledge about factors that determine susceptibility and toxicity is crucial for proper risk assessment.