Atrial fibrillation (AF) is the most common persistent cardiac dysrhythmia and the number one cause of arrhythmia-related hospitalizations. In addition, AF is a major contributor to stroke. With life expectancies increasing, the growing global disability from AF has crippling implications for society. Several family studies have shown a strong polygenetic predisposition for AF but, so far, most of the linkage analysis and candidate gene studies have discovered only monogenic, rare, deleterious mutations. Recent breakthroughs in high-throughput genotyping technology have allowed improved scanning of the genome with greater statistical power to detect susceptibility alleles for AF. Using this technology, a region on 4q25 has now been identified and validated in thousands of cases as a common susceptibility factor for AF with an odds ratio of over 3.0 for homozygotes. The Paired-like homeodomain transcription factor 2 (PITX2) gene, which is involved in embryonic cardiac development, has now been identified as the causal variant for the 4q25 susceptibility locus. Additional susceptibility variants are anticipated that will have direct ramifications for prognosis and treatment of this highly pervasive and clinically significant disorder.