Inadequacies in current therapies for atrial fibrillation have made new drug development crucial. Conventional antiarrhythmic drugs increase the risk of ventricular proarrhythmia. In drug development, the focus has been on favourable multichannel-blocking profiles, atrial-specific ion-channels, and novel non-channel targets (upstream therapy). Molecular modification of the highly effective multichannel blocker, amiodarone, to improve safety and tolerability has produced promising analogues such as dronedarone, although this drug seems less effective than does amiodarone. Vernakalant, an atrial-selective drug with reduced proarrhythmic risk, might be useful for cardioversion in atrial fibrillation. Ranolazine, another atrial-selective agent initially developed as an antianginal, has efficacy for atrial fibrillation and is being tested in prospective clinical trials. So-called upstream therapy with angiotensin-converting enzyme and angiotensin-receptor inhibitors, statins, or omega-3 fatty acids and fish oil that target atrial remodelling could be effective, but need further clinical validation. We focus on the basic and clinical pharmacology of newly emerging antiarrhythmic drugs and non-traditional approaches such as upstream therapy for atrial fibrillation.