Atrial fibrillation (AF) remains a major public health challenge worldwide with a globally increasing prevalence and exponential increase in health care costs. The progression from paroxysmal (defined as self-terminating episodes of AF lasting <7 days) to persistent AF (eg, AF episodes lasting longer than 7 days) is associated with premature mortality, increasing incidence of thromboembolism and heart failure, as well as increased rates of hospitalization and health care use. Given recognition that complications of AF increase as the disease advances, there is an urgent need to ensure therapeutic interventions are capable of delaying or halting disease progression. Whereas pharmacotherapy can be relatively effective at managing the symptoms associated with AF, antiarrhythmic drugs are less effective than catheter ablation in reducing arrhythmia burden, improving quality of life, and reducing health care use. Moreover, pharmacologic therapy does not modify the pathophysiological processes responsible for disease progression. Catheter ablation confers a more comprehensive disease-modifying intervention, targeting multiple mechanisms underlying AF progression through a combination of trigger elimination, electroanatomical substrate modification, and autonomic nervous system modulation. Until recently, the belief that catheter ablation was an effective method to prevent disease progression was mostly speculative. However, recent randomized controlled trials have established catheter ablation as disease-modifying intervention. Given this knowledge, it appears that early intervention is critical to optimally affect the disease progression. The purpose of this paper is to review the rationale and evidence supporting disease modification using catheter ablation as a key part of the AF treatment paradigm.