A variety of cardiac arrhythmias have been attributed to formation of large scale patterns of excitation such as the formation and break up of spiral waves. Atrial fibrillation (AF) is a major cause of morbidity and mortality, for which pharmacologic approaches for rate or rhythm control remain suboptimal. Unravelling the onset and maintenance of atrial arrhythmias depends on details such as geometry, electrical state, anisotropic cellular and subcellular structures. Research has suggested an important role for calcium-dysregulation in AF. To improve our mechanistic understanding, we propose a multi-disciplinary approach, ranging from conventional electrophysiology to, state-of-the-art tissue engineering and optogenetics, and development of novel high speed optical microscopy techniques. The results will allow a better understanding of the basic biological mechanisms of sub-cellular calcium signalling and the aetiology of AF directly relevant in the development of new treatment therapies.