While atrial fibrillation (AF) is the most common sustained cardiac arrhythmia requiring therapy, it is also associated with increased risk of stroke, heart failure, myocardial infarction, dementia, and death. The number of Americans affected with AF is expected to surge to nearly 16 million by the year 2050. The AF epidemic may in part be related to the aging of the population and increasing prevalence of recently identified risk factors including obesity, metabolic syndrome, obstructive sleep apnea, and inflammation. Furthermore, there is increasing support for the idea that both common and rare genetic variants also increase susceptibility to AF which can clinically manifest in the presence of acquired risk factors. While clinical risk factors for AF are established, the genetic components of this "multiple-hit" genetic model for the development of AF have only recently been identified.