Antiarrhythmics are a group of drugs that manage the irregular electrical activity of the heart. Their use in the clinic is made difficult by their narrow therapeutic index. The disposition of antiarrhythmics is dependent on many factors, such as administration route, stereoselectivity in the first-pass effect, inhibition of enzymes, polymorphisms, etc. Consequently, the pharmacological activity of drugs may be interindividually variable. Experiments using organ homogenates or hepatic microsome fractions were used for simulating the biotransformation of the drug in vivo. The classical approaches, such as correlation analysis, specifically the inhibitory effect, or induction of chemicals, and immunoinhibition, may be combined with the use of recombinant enzymes for identifying the enzymes involved in the drug metabolism. The fate of the antiarrhythmics may also be investigated in live animals. A species-dependent metabolism was often observed. The pre-treatment with chemicals, which influences the change (inhibition or induction) in the drug disposition, may provide insights into the enzymes involved in vivo. However, published data indicated that the data obtained from animals should not be extrapolated directly to humans. Nevertheless, animal models are useful for investigating the mechanism of clinical observations. The clinical use of the antiarrhythmics becomes complex, when the drug metabolism is genetically/phenotypically dependent and active metabolites are formed. Furthermore, the stereoselectivity may also modify the disposition and the pharmacodynamic profile of a therapeutic agent. Only the knowledge of the drug metabolism and the status of each individual may allow the use of antiarrhythmics safely.