Atrial fibrillation (AF) is the most common cardiac arrhythmia with a substantial impact on morbidity and mortality. Antiarrhythmic drugs play a major role in rhythm-control therapy of AF. However, currently available agents exhibit limited efficacy and pronounced adverse effects, notably drug-induced proarrhythmia. Recent experimental studies have identified that Ca2+ handling abnormalities are critical elements in AF pathophysiology with central roles in atrial ectopic activity, reentry, and atrial remodeling suggesting that Ca2+ handling abnormalities could be promising targets for novel AF therapeutics. Here, we summarize key aspects of AF-related Ca2+-handling abnormalities, describe currently available compounds targeting atrial Ca2+ handling, and highlight potential novel targets and experimental drugs currently under investigation. Finally, we assess how close AF therapeutics based on Ca2+-handling abnormalities are to clinical implementation.