Atrial fibrillation (AF) is an important cause of stroke and risk factor for heart failure and death. Current pharmacologic treatments for AF have limited efficacy, and treatments that more directly target the underlying causes of AF are needed. Oxidant stress and inflammatory activation are interrelated pathways that promote atrial electrical and structural remodeling, leading to atrial ectopy, interstitial fibrosis, and increased stroke risk. This review evaluates the impact of common stressors on atrial oxidant stress and inflammatory activation and the contribution of these pathways to atrial remodeling. Recent studies suggest that integrated efforts to target the underlying risk factors, rather than the AF per se, may have a greater impact on health and outcomes than isolated efforts focused on the electrical abnormalities.