Ablation of atrial fibrillation is an established treatment for the management of patients with paroxysmal and persistent atrial fibrillation. The complex pathophysiology of persistent atrial fibrillation has fuelled the concept of adjunctive substrate modification on top of pulmonary vein isolation. However, recent studies have failed to demonstrate additive benefit from complex ablation approaches, thus supporting that standalone pulmonary vein isolation may prove sufficient, at least as the initial ablation strategy in persistent atrial fibrillation. In this premise, the new-generation cryoballoon is an attractive option in this demanding subgroup of patients due to its reliable efficacy in achieving pulmonary vein isolation combined with collateral debulking of the neighbouring atrial myocardium. In this review, we present a critical appraisal of the role of cryoablation in patients with persistent atrial fibrillation, discussing related technical considerations and existing scientific evidence.