Abnormal calcium (Ca) handling can contribute to arrhythmogenesis directly by triggering abnormal depolarizations and indirectly by modulating action potential time course and duration. Recent data have shown the importance of these mechanisms in rare genetic diseases but also in more common conditions such as heart failure. Modulating Ca release from the sarcoplasmic reticulum via the ryanodine receptor, Ca uptake via sarcoplasmic reticulum Ca ATPase or Ca removal from the cell via the Na/Ca exchanger, are potential approaches to reduce arrhythmias. New tools allow exploring these ideas. The principles underlying this approach and the first results are critically reviewed.