Despite recent advances in catheter-based and surgical therapies, anti-arrhythmic drugs (AADs) remain the mainstay of treatment for patients with symptomatic AF. However, response in an individual is highly variable with more than half of patients treated with AADs suffering a recurrence of AF within 6 to 12 months. The limited success of therapy for AF is related to poor understanding of the underlying pathophysiology, heterogeneity of the electrical and structural substrate, and the lack of targeted mechanism-based therapies. Thus, one major knowledge gap is predicting response to AADs in an individual patient. Contemporary membrane-active drugs used to suppress AF are incompletely and unpredictably effective and are associated with significant risks of proarrhythmia and non-cardiac toxicities. Furthermore, the current 'one-size fits all' approach to selecting AAD therapy for a patient with symptomatic AF is based largely on minimizing the risk of adverse events rather than on the likelihood of efficacy. Recent advances in our understanding of genetic mechanisms of AF support the overarching hypothesis we wish to test in future studies that variability in response to AAD therapy is modulated by common genetic variants associated with AF. Several AF susceptibility loci have been identified and validated in genome-wide association studies. In addition, we have shown that common AF risk single nucleotide polymorphisms (SNPs) at the chromosome (chr) 4q25 locus not only predict poor response to AADs but also recurrence of AF after ablation therapy and cardioversion.