A young science serves its purpose if it leads not only to new knowledge, but to new insights and concepts. This article opens with examples to illustrate some former thinking that the introduction of pharmacogenetic has overcome. Pharmacogenetic case histories from discovery to the present illustrate the interlocking of observations, technical advances, and changing concepts. There are striking biological similarities between pharmacogenetics and those inborn factors that cause resistance to infectious disease: Both represent person-to-person variations that may help the survival of populations, one when facing massive toxic exposures, the other when facing plagues and epidemics. Thus pharmacogenetics represents a biologically necessary variability of the defenses against chemical intruders, and this includes drugs. While this variability is desirable, drug toxicity occurring on the basis of this variability must be avoided. The most successful defendants against toxicity due to polymorphic (ie, high incidence) variants should be the designers of new drugs. The only defender concerned with rare variants can be the attentive clinician.
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