After the sequential successes of catheter ablation for the treatment of pre-excitation syndromes (WPW), junctional reentry (AVNRT) atrial flutter (AFL) and ventricular arrhythmias, clinical electrophysiologists have focused on the myocardial basis of atrial fibrillation (AF). Thus, the strategy for ablation of drug and cardioversion refractory AF was to isolate the myocardial connections from the focal firing pulmonary veins (PVs) in addition to altering the atrial substrate maintaining AF. However, the overall success rates have not achieved those of the other types of ablation procedures. In this review we have summarized the favorable aspects and drawbacks of pulmonary vein isolation (PVI). As for the role of the Intrinsic Cardiac Autonomic Nervous System (ICANS), both basic and clinical evidence has shown that ganglionated plexi (GP) stimulation promotes initiation and maintenance of AF, and that GP ablation reduces recurrence of AF following catheter or surgical ablation of these structures. Based on these findings, the GP Hyperactivity Hypothesis has been proposed to explain, at least in part, the mechanistic basis for the focal form of AF. For example, PV isolation may not always be necessary for elimination of AF, as in the early stages of paroxysmal AF. GP ablation alone, in these cases, may suffice for focal AF termination. In the persistent and long standing persistent forms the substrate for AF may be more extensive and therefore require GP ablation plus PV isolation and/or CFAE ablations. Clinical reports, both catheter based as well as minimally invasive surgical procedures, which include PVI plus GP ablation have shown relatively long-term success rates much closer to or equal to those achieved by myocardial ablation procedures in patients with WPW, AVNRT and AFL.