Atrial fibrillation (AF) is a very common arrhythmia. Currently available tools to control arrhythmic recurrences (antiarrhythmic agents, catheter ablation) are not entirely satisfactory. Recently attention has been directed to upstream therapy, in order to alter the arrhythmia substrate; the most promising drugs seem to be those targeting the renin-angiotensin-aldsterone system. Several post-hoc analyses from large trials, in different clinical situations, confirmed the efficacy of angiotensin-converting enzyme-inhibitors and angiotensin II receptor blockers in primary prevention of AF. On the contrary prospective randomized, placebo-controlled, and double-blind studies showed negative results as for secondary prevention of AF. The GISSI-AF trial, the largest study (1442 patients) dealing with the use of angiotensin II receptor blockers in prevention of AF recurrences, has not demonstrated any difference between patients treated with valsartan (51.4% AF recurrences in a 12-month follow-up) vs. the placebo group (52.1%, p = NS). Therefore, available data do not support the use of these drugs in secondary prevention of AF.