The occurrence of post-operative atrial fibrillation (POAF) requires the presence of an electrophysiological substrate that is the consequence of multiple re-entry wavelets resulting from the dispersion of atrial refractoriness. The latter requires an atrial structural substrate, which might be the consequence of an association of multiple predisposing factors (advanced age, hypertension, diabetes, obesity, left atrial enlargement, and left ventricular hypertrophy). Alternatively, operative and post-operative factors such as atrial ischemia and surgical atrial injury might also contribute to the development of the structural substrate. Inflammation and oxidative stress also seem to play an important role. Finally, genetic factors likely predispose some patients to the development of POAF. Once these conditions are present, a triggering factor such as an atrial premature contraction, electrolyte imbalance, and/or enhanced adrenergic or vagal stimulation will initiate POAF.