In this review we focus on the impact of genetic admixture on pharmacogenomics in the American continent, where five centuries of intermarriage between Amerindians, European and Africans, resulted in the extensive population heterogeneity observed nowadays. We compare two alternative views of human genomic variation, one stressing populations and the other stressing individuals, and discuss their important and far-reaching consequences to implementation of pharmacogenetics/genomics in practice, especially when dealing with admixed populations. We conclude that a variable mosaic genome paradigm, which envisages the genome of any particular individual as a unique mosaic of variable haplotype blocks - has considerably higher explanation and predictive power for the populations of the Americas. We then move to the more formal pharmacogenomics arena to examine the pharmacogenetic/pharmacogenomic diversity in the Americas and review the challenges and advantages of admixed populations for pharmacogenomic studies. Because interethnic admixture is either common or increasing at a fast pace in many, if not most populations, extrapolation on a global scale of pharmacogenomic data from well-defined ethnic groups is plagued with uncertainty. Intra-ethnic diversity adds complexity to the scientific appraisal, regulatory decisions and, eventually, prescribing of drugs purportedly targeted to a given “race” or ethnicity. Pharmacogenetics/ genomics has the potential to benefit people worldwide and to reduce the health disparities between developing and developed nations. This goal is unlikely to be achieved by relinquishing the notion of personalized drug therapy tailored to individual genetic characteristics - the original promise of pharmacogenetics - in favor of a model (pharmacogenomic?) of population-based drug development and prescription, with all its potential pitfalls, especially when extended to admixed populations in developing or developed nations.