The toxicity that can result from the exposure to numerous xenobiotics can vary greatly for each individual. This is mainly due to differences in the activity of xenobiotic metabolizing enzymes (XME) that participate in the disposal of toxic xenobiotics from the human body. The genes that encode XMEs present a variety of polymorphisms that occur in the promoter or coding regions, resulting in differences in the amount or in the catalytic activities of the enzymes. Human populations differ regarding the frequency of alleles and haplotypes that are present in a given geographic region. Genetic background and ancestry are the main reasons for such variability. South America, due to an extensive colonization period, is populated by descendents of Amerindians, Africans and Europeans. The admixtures that happened in each country, however, vary according to historical and geographical conditions. Brazil, for example, has one of the worlds most admixed populations with genetic contributions from several tribes of Amerindians, many still existent, from Africans, and from various waves of European immigrants. In this review we will discuss the frequency of genetic polymorphisms of XMEs, particularly Cytochrome P450s and Glutathione S-transferases, found in different populations of South American countries. The genetic background and degree of population admixture of each country is taken under consideration in a discussion of the difficulties generated by enzyme polymorphisms in the treatment of individuals within such populations.