Atrial fibrillation (AF), the most prevalent arrhythmia, is often associated with enhanced inflammatory response. Emerging evidence points to a causal role of inflammatory signaling pathways in the evolution of atrial electrical, calcium handling and structural remodeling, which create the substrate of AF development. In this review, we discuss the clinical evidence supporting the association between inflammatory indices and AF development, the molecular and cellular mechanisms of AF, which appear to involve multiple canonical inflammatory pathways, and the potential of anti-inflammatory therapeutic approaches in AF prevention/treatment.