Significance Transition metals are micronutrients that all organisms use in essential metabolic processes. The ubiquitous Natural resistance-associated macrophage protein (Nramp) family facilitates the acquisition of these metal ions by transporting them across cellular membranes, including dietary iron absorption in mammals. We show that a conserved methionine, an unusual metal-binding residue found in the Nramp metal-binding site, is not essential for the transport of physiological environmentally scarce transition metals like iron and manganese. Instead, it confers selectivity against the abundant alkaline earth metals calcium and magnesium, with the tradeoff of making the toxic metal cadmium a preferred substrate. Using protein structure information, biochemical results, molecular dynamics simulations, and inorganic chemistry theory, we propose a model for how metal discrimination is enforced.