We analyzed strontium isotopes in more than 500 samples of shell, bone, and dental enamel from modern and archaeological contexts throughout Mesoamerica. The results correspond closely with expectations based upon the local geology and earlier measurements of geological materials. The results show that isotopic variation is significant across Mesoamerica. Thus strontium isotope ratios in dental enamel, which mark the place of childhood residence, can be used not only to document mobility but also in some cases to determine geographic origin. We present five archaeological case studies to illustrate the anthropological significance and range of applications for this technique: the origins of individuals in the Oaxaca Barrio at Teotihuacan, a northern origin for the founder of Copan, a local king at Tikal, the regional origin of two of Palenque's rulers, and individuals of African birth in a colonial cemetery in Campeche.