Individuals vary widely in their responses to therapy with most drugs. Indeed, responses to antiarrhythmic drugs are so highly variable that study of the underlying mechanisms has elucidated important lessons for understanding variable responses to drug therapy in general. Variability in drug response may reflect variability in the relationship between a drug dose and the concentrations of the 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 a 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 biological context in which the drug-target interaction occurs. Variants (polymorphisms and mutations) in the genes that encode proteins that are important for pharmacokinetics or for pharmacodynamics have now been described as important contributors to variable drug actions, including proarrhythmia, and these are described in this review. However, the translation of pharmacogenetics into clinical practice has been slow. To this end, the creation of large, well-characterised DNA databases and appropriate control groups, as well as large prospective trials to evaluate the impact of genetic variation on drug therapy, may hasten the impact of pharmacogenetics and pharmacogenomics in terms of delivering personalised drug therapy and to avoid therapeutic failure and serious side effects.