This chapter discusses methodological issues relevant to conducting pharmacogenetic studies in clinical psychopharmacology. First, basic pharmacologic principles are reviewed, followed by a discussion of the drug development process. In addition to aiding in the drug discovery process, pharmacogenetic finding would also help with the signal:noise problem, at the human testing phase of drug development (that is, phase I through III). Scientists can select the specific subset of the population (that is, those with the genetic variant) likely to respond to the drug. The chapter reviews the significant potential for advancing psychiatric drug development as a result of improved understanding of the pharmacogenetics and pharmacogenomics relevant to the effects of drugs on the human brain. Last, the research linking cytochrome P-450 CPY2D6 poor metabolizers with increased risk of toxicity on routine doses of tricyclic antidepressants (TCAs) are reviewed as an example of the methodological issues encountered when conducting such studies.