Three underappreciated concepts having an important impact on the use of antiarrhythmic agents having Class I activity are discussed. These are stereochemical influences on antiarrhythmic action, the modulated receptor theory, and pharmacogenetics. The stereoisomers of some antiarrhythmic agents behave differently in terms of their potency, disposition, and antiarrhythmic action. For example, the enantiomers of both tocainide and mexiletine are cleared at different rates, and those of disopyramide have opposite effects on repolarization. The modulated receptor theory suggests that the affinity of antiarrhythmic drugs to bind to a specific receptor on or near the sodium channel depends on whether the sodium channel is open, resting, or inactivated. Study of the interaction between the state of the sodium channel and the differing actions of the antiarrhythmic agents have provided evidence for synergistic drug combinations. Pharmacogenetics relates to the differences observed in drug metabolism among individuals, which can result in variations of two- to fourfold in clearance and plasma concentration in some cases. There is still much to learn about Class I antiarrhythmic agents. These concepts should lead to a better understanding of their actions and increase their utility.