Atrial fibrillation (AF) affects 1.5-2.0% of the population in the developed world. Projected data from population-based studies in the US indicate that the number of adults with AF will swell by 2.5-3.0-fold by 2050. Despite advances in pharmacological and nonpharmacological therapies for rhythm or rate control in patients with AF, primary prevention with 'upstream' therapy and risk factor modification is likely to produce a far greater effect in the general population than specific interventions. Rapidly developing experimental work has provided new insights into AF pathophysiology that will lead to new mechanism-based therapies. Agents targeting inflammation, oxidative injury, atrial myocyte metabolism, extracellular matrix remodeling, and fibrosis, have theoretical advantages as novel therapeutic strategies. Angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, statins, and omega-3 polyunsaturated fatty acids have shown antiarrhythmic potential, over and above any effect related to the treatment of underlying heart disease. These agents could be exploited to prevent or delay atrial remodeling in patients with AF, even in the absence of routine indications for such therapy. This Review provides a contemporary evidence-based insight into the possible preventive and reverse remodeling roles of statins and polyunsaturated fatty acids in AF.