Research into the pathophysiology of AF has produced enormous advances in our understanding of the arrhythmia. These include insights into the basis of ectopic activity, determinants of atrial reentry, atrial remodeling, and genetic determinants. Atrial ectopic activity is enhanced by AF-related remodeling, with the principal underlying mechanism being Ca2+-handling abnormalities leading to abnormal diastolic Ca2+-releases from the sarcoplasmic reticulum (SR). A central feature is dysfunction of the SR ryanodine-receptor (RyR) Ca2+-release channel, due primarily to calcium/calmodulin-dependent kinase II (CaMKII) hyperphosphorylation. Reentry substrate-generation may result from refractory-period abbreviation due to reduced inward L-type Ca2+ current (ICaL) or enhanced outward K+ current. The rapid atrial activation-rates during AF reduce ICaL and increase inward-rectifier K+-currents (background IK1 and constitutive acetylcholine-dependent K+-current IKACh). A common mediator is cellular Ca2+loading and consequent signaling, particularly via the Ca2+/calcineurin-NFAT system. Another contributor to reentry substrates is structural remodeling, like changes in atrial tissue-composition (fibrosis), loss/dyslocalization of cell-coupling connexin-channels and atrial dilation. Autonomic dysfunction is also an important contributor. Genetic /molecular-pathophysiology studies have provided insights by revealing the basis of monogenic familial AF and clarifying the complex predisposing heritable factors in the population. These new findings have resulted in the development of novel therapeutic options. Novel drug-therapies target atrial-selective ion-channels (like IKACh, IKur and ISK) and the mechanisms involved in ectopic-activity generation, like RyR-release abnormalities and CaMKII-signaling. Insights into the molecular basis of atrial remodeling has led to “upstream therapy”, which has shown promise in improving the natural history of AF. Mechanism-based ablation-approaches include targeting cardiac innervation and AF-maintaining rotors. Agents being developed include classical small-molecule drugs, along with newer approaches like modulation of microRNA-pathways and gene/cell-therapy. Finally, studies of genetic associations and biomarkers promise new inroads into risk prediction and stratification, and ultimately personalized individual-patient based treatment.