Atrial fibrosis appears to be a key factor in the genesis and/or perpetuation of atrial fibrillation (AF). The pathological distribution of atrial fibrosis is geographically consistent with the attachments between the posterior left atrium and the pericardium along the reflections where wall stiffness is increased and structural changes are found. While there is a wide range of complex etiological factors and electrophysiological mechanisms in AF, there is evidence for a common pathophysiological pathway that could account for deliberate substrate formation and progression of AF. Anatomical stresses along the atrium, mediated by the elastic modulus mismatch between atrial tissue and the pericardium, result in inflammatory and fibrotic changes which create the substrate for atrial fibrillation. This may explain the anatomical predominance of pulmonary vein triggers earlier in the development of atrial fibrillation and the increasing involvement of the atrium as the disease progresses. Ablative treatments that address the progressive nature of atrial fibrillation and fibrosis may yield improved success rates.