By 2050, atrial fibrillation (AF) will be present in 2% of the general population and in a far higher proportion of elderly patients. Currently, we are content with rate control and anticoagulation in elderly asymptomatic patients, whereas in younger patients with symptomatic recurrent AF, pulmonary vein isolation is the treatment of choice. However, in a large number of patients, there remains a genuine choice between anti-arrhythmic therapy to suppress the arrhythmia and rate control to control the ventricular rate. This review provides a contemporary evidence-based insight into the buoyant development of new anti-arrhythmic agents, exploring new mechanisms of action or novel combinations of established anti-arrhythmic activity. An attractive prospect for AF therapy is the introduction of agents with selective affinity to ion channels specifically involved in atrial repolarization, so-called atrial repolarization-delaying agents. Presently, there are several potential anti-arrhythmic drugs with this mode of action, which are currently in pre-clinical and clinical development. Vernakalant is in the most advanced phase of investigation and its intravenous formulation has recently been recommended for approval for pharmacological cardioversion of AF. However, although this agent has some electrophysiological effects which are specific to the atria, it has others which affect both the atria and the ventricles. Other drugs, such as XEND0101, block a single atrial-specific membrane current. The success of such agents depends critically on their atrial electrophysiological selectivity, freedom from cardiac adverse effects, and general safety. Other possibilities include modified analogues of traditional anti-arrhythmic drugs with additional novel mechanisms of action and less complex metabolic profiles. Dronedarone is an investigational agent with multiple electrophysiological effects, which is devoid of iodine substituents and is believed to have a better side effect profile than its predecessor amiodarone. The development portfolio of dronedarone is practically complete and approval for several indications in AF may soon be assessed. Innovative anti-arrhythmic agents with unconventional anti-arrhythmic mechanisms, such as stretch receptor antagonism, sodium-calcium exchanger blockade, late sodium channel inhibition, and gap junction modulation, have not yet reached clinical studies in AF. Gene- and cell-based therapies, which can selectively target individual currents, could provide ideal one-time only curative therapy for arrhythmias, and the first proof-of-concept studies have been reported. There is accumulating evidence in support of the anti-arrhythmic effects of non-anti-arrhythmic drugs. Treatments with angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, statins, and omega-3 fatty acids all seem promising, over and above any effect related to the treatment of underlying heart disease. However, despite exciting results from animal experiments and promising outcomes from retrospective analyses, there is no robust evidence of specific effects of these drugs to transform current clinical practice.