Intensive research over the last few decades has seen significant advances in our understanding of the complex mechanisms underlying atrial fibrillation (AF). The epidemic of AF and related hospitalizations has been described as a ‘rising tide’ with estimates of the global AF burden showing no sign of retreat. There is urgency for effective translational programs in this field to facilitate more individualized and targeted therapy to modify the abnormal atrial substrate responsible for the perpetuation of this arrhythmia. In this review, we chose to focus on several novel aspects of AF pathogenesis whereby practical applications in clinical practice are currently available or potentially not too far away. Specifically, we explored the contribution of atrial fibrosis, epicardial adipose tissue, autonomic nervous system, hyper-coagulability, and focal drivers to adverse atrial remodelling and AF persistence. We also highlighted the potential practical means of monitoring and targeting these factors to achieve better outcomes in patients suffering from this debilitating illness. Emerging data also support a new paradigm for targeting AF substrate with aggressive risk factor management. Finally, multi-disciplinary integrated care approach has shown great promise in improving cardiovascular outcomes of patients with AF along with potential cost savings.