Humans vary widely in their response to drug therapy. This may reflect variability in the relationship between a drug dose and the concentrations of drug and metabolite(s) at relevant target sites; this is termed pharmacokinetic variability. Another mechanism is that individuals vary in their response to identical exposures to drug (pharmacodynamic variability). In this case, there may be variability in the target molecule(s) with which a drug interacts, or more generally in the broad biologic context in which the drug-target interaction occurs; for example, ischemia, electrolyte disturbances, or hypertrophy can all modulate drug effects. Variants in the genes encoding proteins important for pharmacokinetics or for pharmacodynamics have now been described as important contributors to variable drug actions, including proarrhythmia, and are described here. These increasingly well-recognized examples have two important implications; first, it may be possible to develop drugs devoid of heretofore-unexplained adverse effects and, second, it may become possible to preselect drug for individual patients based on specific genetic factors.