Abnormalities of cardiac rhythm are common clinical problems, resulting in symptoms such as palpitations, breathlessness, stroke, and sudden death. Drugs used to treat arrhythmias have variable actions ranging from completely effective to serious adverse effects, including (paradoxically) sudden death due to drug-induced arrhythmias. Experiments to define the genetic basis for arrhythmia susceptibility and variable responses to antiarrhythmic therapies rely on precise clinical phenotyping. Initial studies used candidate gene approaches, but are now turning to contemporary methods such as genome-wide association. Identification of loci for arrhythmia susceptibility in turn provide a starting point for both understanding underlying biologic pathways as well as improved selection appropriate therapies.