How different classes of anti-arrhythmia drugs interact with cardiac sodium channels in order to make them work efficiently is revealed in Nature Communications this week. The work could potentially aid the design of new drugs to treat cardiac arrhythmias.Anti-arrhythmic drugs are used widely in the clinic, and different classes are used to treat different types of arrhythmia. Class I anti-arrhythmic drugs act at cardiac sodium channels and are subdivided into classes based on their effects on the electrocardiogram. However, the molecular basis of these subclassifications is poorly understood. Christopher Ahern and co-workers find that class Ib anti-arrhythmia drugs bind to sodium channels via a strong electrostatic cation-pi interaction, whereas class Ia and Ic anti-arrhythmia drugs rely significantly less on this interaction. These detailed molecular insights may aid the discovery of new anti-arrhythmia drugs.