Atrial fibrillation (AF) is the most common cardiac arrhythmia, and is responsible for the highest number of rhythm-related disorders and cardioembolic strokes worldwide. Early management of this condition will lower the risk of AF-associated morbidity and mortality. Targeted drug therapy has an important role in preventing the progression of AF through modification of the substrate. Discovery of the role of pulmonary veins as a trigger has been an important breakthrough, leading to the development of pulmonary vein ablation—an established curative therapy for drug-resistant AF. Identifying the underlying reasons for the abnormal firing of venous cardiomyocytes and the widespread progressive alterations of atrial tissue found in persistent AF are challenges for the future. Novel imaging techniques may help to determine the right time for intervention, provide specific targets for ablation, and judge the efficacy of treatment. If new developments can successfully address these issues, the knowledge acquired as a result will have a vital role in preclinical and early management of AF.