Post-operative atrial fibrillation (POAF) is a frequent complication occurring in 30% to 50% of patients after cardiac surgery. It is associated with an increased risk of mortality and morbidity, predisposes patients to a higher risk of stroke, requires additional treatment, and increases the costs of the post-operative care. The aim of this review is to present the current state of knowledge about the risk factors, mechanisms, prevention, and treatment of this complication. In addition to the well known risk factors for the development of POAF such as age, left atrial enlargement, and valvular surgery, new metabolic risk factors related to visceral obesity have been identified. With regard to the prevention of POAF, beta-blocker drugs are effective and safe and can be used in most patients, whereas amiodarone can be added in high-risk patients. Biatrial pacing was shown to be effective; however, its complexity might limit its application. Although there are only few data regarding the usefulness of magnesium, statins, N-3 polyunsaturated fatty acids, and corticosteroids, their addition to beta-blocker drugs might be of benefit for further reducing POAF. Treatment includes the use of an AV nodal blocking agent to achieve the rate control. If AF does not spontaneously convert to sinus rhythm within 24 h, anticoagulation should be initiated and a rhythm control strategy should be attempted. More investigations are warranted to explore mechanisms by which POAF occurs. This new knowledge would undoubtedly translate into a more efficient prevention and treatment of this common post-operative complication that is associated with a major health and economic burden.