Current evidence suggests that the pathogenesis of atrial fibrillation (AF) is multifactorial. The observation that AF, once present, alters the electrophysiologic properties of the atrial myocardium causing self-perpetuation of the arrhythmia raised the importance of electrical remodeling in its pathogenesis. Although these changes are potentially reversible, maintenance of AF continues even after electrical remodeling has occurred. Clinical and experimental studies have highlighted the role of a susceptible atrial anatomical substrate with features of myocyte degeneration and interstitial fibrosis in the initiation and maintenance of AF. Finally, the association of increased inflammatory burden with the presence and future development of AF has implicated inflammation in the pathogenesis of the arrhythmia. The purpose of this review is to provide current evidence on the dominant theories on AF pathogenesis, namely, electrical remodeling, structural remodeling, and inflammation; describe the various experimental models and methods used; and identify a cause-effect association, when present. In addition, the interrelation between different mechanisms responsible for AF will be demonstrated, providing further insight into the complex pathophysiology.