Atrial fibrillation (AF) is an extremely prevalent arrhythmia that presents a wide range of therapeutic challenges. AF usually begins in a self-terminating paroxysmal form (pAF). With time, the AF pattern often evolves to become persistent (nonterminating within 7 days). Important differences exist between pAF and persistent AF in terms of clinical features, in particular the responsiveness to antiarrhythmic drugs and ablation therapy. AF mechanisms have been extensively reviewed, but few or no Reviews focus specifically on the pathophysiology of pAF. Accordingly, in this Review, we examine the available data on the electrophysiological basis for pAF occurrence and maintenance, as well as the molecular mechanisms forming the underlying substrate. We first consider the mechanistic insights that have been obtained from clinical studies in the electrophysiology laboratory, noninvasive observations, and genetic studies. We then discuss the information about underlying molecular mechanisms that has been obtained from experimental studies on animal models and patient samples. Finally, we discuss the data available from animal models with spontaneous AF presentation, their relationship to clinical findings, and their relevance to understanding the mechanisms underlying pAF. Our analysis then turns to potential factors governing cases of progression from pAF to persistent AF and the clinical implications of the basic mechanisms we review. We conclude by identifying and discussing questions that we consider particularly important to address through future research in this area.