Atrial fibrillation (AF) is the most common sustained arrhythmia in adults. Current limitations of pharmacological and ablative therapies motivate the development of novel therapies as next generation treatments for AF. The arrhythmia mechanisms creating and sustaining AF are key elements in the development of this novel treatment. Gene therapy provides a useful platform that allows us to regulate the mechanisms of interest using a suitable transgene(s), vector, and delivery method. Effective gene therapy strategies in the literature have targeted maladaptive electrical or structural remodeling that increase vulnerability to AF. In this review, we will summarize key elements of gene therapy for AF, including molecular targets, gene transfer vectors, atrial gene delivery and preclinical efficacy and toxicity testing. Recent advances and challenges in the field will be also discussed.