During atrial fibrillation, abnormal high-frequency activation induces 'remodeling' of the atrial myocardium, which includes changes in both electrical and structural properties. Substantial progress in understanding the molecular determinants underlying atrial fibrillation has led to the development of drugs that could enhance the long-term efficacy and safety of treating this common cardiac arrhythmia. New therapeutic approaches aim to prevent atrial remodelling, especially structural remodelling, improve currently used drugs, and design atria- and pathology-specific drugs without concomitant pro-arrhythmic effects in the ventricles. Considerable progress has been made in elucidating the molecular mechanisms of atrial fibrillation. However, a major improvement in the pharmacotherapy is still awaited. The promising efficacy of several new drugs in animal models of atrial fibrillation has yet to be demonstrated in clinical studies.