Despite impressive advances in the therapy of a number of types of heart disease in the last two decades, sudden cardiac death remains a public health problem of staggering dimensions. Current treatment options include antiarrhythmic drugs that have higher than desired failure rates and implantable defibrillators that incur significant costs to the patient and society. The development of therapies that better suppress the cardiac arrhythmias responsible for sudden cardiac death requires a broad and comprehensive understanding of the basic mechanisms underlying electrical instability in the heart. This study explores the scientific basis for a molecular genetic approach to modify cardiac excitability and thereby to create animal models of sudden cardiac death. The availability of such models will open up new avenues of research in arrhythmogenesis and facilitate the development of novel antiarrhythmic agents.