The figure depicts the conceptual model of the pathogenesis and progression to AF over the lifetime of individuals at risk. Understanding the pathophysiological contributors to AF onset will enhance opportunities for discovering effective AF prevention strategies. Risk factors and cardiovascular subclinical disease contribute to structural and electrical remodeling AF. Risk factors (upper yellow box) have bidirectional relations with alterations in cardiovascular structural substrates such as inflammation, fibrosis and remodeling. Risk factors also contribute to the development of subclinical cardiovascular diseases, which can be detected by noninvasive modalities such as imaging, biomarkers and genomics. Subclinical diseases (upper turquoise box) contribute to the development of clinical disease such as heart failure and myocardial infarction, which can precipitate AF. Similarly, structural alterations (lower yellow box) lead to electrical remodeling (lower turquoise box). Both clinical cardiovascular disease and electrical remodeling contribute to the triggers (lower blue box), which initiate AF. AF may progress to complications (pink box). The prevention of AF may occur at multiple points along the causal pathways, such as lifestyle and therapeutic interventions to prevent and treat risk factors, structural substrate alterations, subclinical perturbations, electrical remodeling, and clinical cardiovascular disease. Once AF is initiated, secondary prevention efforts will focus on preventing the development of persistent forms of AF.