Although paroxysmal atrial fibrillation (AF) is known to be initiated by rapid firing of pulmonary veins (PV) and non-PV triggers, the crucial role of cardiac autonomic nervous system (ANS) in the initiation and maintenance of AF has long been appreciated in both experimental and clinical studies. The cardiac intrinsic ANS is composed of ganglionated plexi (GPs), located close to the left atrium-pulmonary vein junctions and a vast network of interconnecting neurons. Ablation strategies aiming for complete PV isolation (PVI) remain the cornerstone of AF ablation procedures. However, several observational studies and few randomized studies have suggested that GP ablation, as an adjunctive strategy, might achieve better clinical outcomes in patients undergoing radiofrequency-based PVI for both paroxysmal and nonparoxysmal AF. In these patients, vagal reactions (VR) such as vagally mediated bradycardia or asystole are thought to reflect intrinsic cardiac ANS modulation and/or denervation. Vagal reactions occurring during cryoballoon- (CB-) based PVI have been previously reported; however, little is known on resulting ANS modulation and/or prevalence and significance of vagal reactions during PVI with the CB technique. We conducted a review of prevalence, putative mechanisms, and significance of VR during CB-based PVI.