In a few cases, alleles at single gene loci have a major effect on adverse drug reactions and therapeutic failures. More often, the relationship is complex. Predictive values of putative pharmacogenetic tests for variant alleles (or associated polymorphisms) are seldom very high. This chapter considers how the role of genes in drug-handling is established and examines the frequency of inherited variants related to drug handling and the strength of their association with altered drug-handling. In view of the often weak associations between variant alleles and altered drug handling, regulation of pharmacogenetic tests is of utmost importance.