Atrial fibrillation is a prominent cause of morbidity and mortality in developed countries. Treatment strategies center on controlling atrial rhythm or ventricular rate. The need for anticoagulation is an independent decision from the rate versus rhythm control debate. This review discusses novel biological strategies that have potential utility in the management of atrial fibrillation. Rate controlling strategies predominately rely on G-protein gene transfer to enhance cholinergic or suppress adrenergic signaling pathways in the atrioventricular node. Calcium channel blocking gene therapy and fibrosis enhancing cell therapy have also been reported. Rhythm controlling strategies focus on disrupting reentry by enhancing conduction or suppressing repolarization. Efforts to suppress inflammation and apoptosis are also under study. Resistance to blood clot formation has been shown with thrombomodulin. These strategies are in various stages of preclinical development.