Atrial fibrillation (AF) is the most common cardiac arrhythmia, contributing to increased morbidity and reduced survival through its associations with stroke and heart failure. AF contributes to a four- to fivefold increase in the risk of stroke in the general population and is responsible for 10-15 % of all ischemic strokes. Diagnosis and treatment of AF require considerable health care resources. Current therapies to restore sinus rhythm in AF are suboptimal and are limited either by their pro-arrhythmic effects or by their procedure-related complications. These limitations have necessitated identification of newer therapeutic targets to expand the treatment options. There has been a considerable amount of research interest in investigating the mechanisms of initiation and propagation of AF. Despite extensive research focused on the pathogenesis of AF, a thorough understanding of various pathways mediating initiation and propagation of AF still remains limited. Research efforts focused on the identification of these pathways and molecular mediators have generated a great degree of interest for developing more targeted therapies. This review discusses the potential therapeutic targets and the results from experimental and clinical research investigating these targets.