Recent insights in the molecular nature of genetic arrhythmia syndromes, as well as more common conditions such as heart failure, have demonstrated a link between abnormal calcium (Ca²⁺) handling and ventricular arrhythmias. Mechanistically, abnormal Ca²⁺ can contribute to arrhythmogenesis by triggering delayed afterdepolarizations, and/or by modulating the duration and time course of the action potential. In both scenarios, the Na/Ca exchanger (NCX) has a pivotal role, and thus partial NCX block is a potential antiarrhythmic strategy. This is currently being explored in a number of arrhythmia diseases using a new generation of NCX blockers with improved potency and selectivity, such as SEA0400. Because the NCX is essential for maintaining proper Ca²⁺ balance of the cardiac cell, the functional consequences of NCX block on Ca²⁺ handling should be carefully considered. We have addressed this by studying Ca²⁺ handling in heterozygous NCX knockout mice with reduced cardiac NCX expression and function, and by using pharmacological approaches in large animal models of proarrhythmia. Finally, our newest findings with SEA0400 as an antiarrhythmic agent in a dog model of triggered arrhythmias related to abnormal repolarization and enhanced NCX activity, will be presented.