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Age-related, progressive arrhythmia atrial fibrillation (AF) is the cardiovascular epidemic of the 21th century. The increase in the number of patients with AF is associated with the ageing of populations suffering from a variety of cardiovascular diseases because of the improved clinical care. The development of AF depends on the presence of triggers, initiators, and substrates, and is treated with drugs, implantable devices (electrical stimulation/defibrillation therapy), and catheter-based ablative therapy. Unfortunately, the currently available therapies are moderately effective and can have serious side-effects. There are several explanations for therapy failure. In case of trigger-driven AF, recurrences after ablative therapy are the result of a reconduction across the ablation lesions. In substrate-mediated patients, AF is caused by “electropathology”, which is defined as abnormalities in electrical impulse formation or conduction as a result of the structural damage of cardiac tissue. The exact electrical and molecular mechanisms underlying AF are at present only partly known. The severity of electropathology determines which treatment modality is the most effective, and is therefore indispensable in guiding therapy. However, there are insufficient (pharmaco) therapeutic tools to target the underlying electropathological substrate. Hence, the development of patient-tailored diagnostic tools and innovative therapies is of paramount importance in order to improve arrhythmia-free survival. In the past decades, many novel therapies for patients with AF have been developed with a variety of targets, ranging from the prevention of thrombo-embolic complications, to complex ablation strategies. The aim of this Special Issue is to discuss the contribution of novel approaches to advances in the management of patients with AF.