Using optical mapping of voltage sensitive dyes in experimental studies of acute atrial fibrillation (AF) in the isolated sheep heart in the presence of acetylcholine (ACh) or increased intra-atrial pressure demonstrate that high-frequency reentrant sources in the posterior wall of the left atrium drive the fibrillatory activity throughout both atria. In humans, however, direct visualization of rotors is possible but is far more challenging than in animals. We therefore have focused our analysis in humans on the distribution of dominant frequencies (DFs) during AF to gain mechanistic and therapeutic insight. Using electro-anatomic mapping and Fourier spectral methods we generated three-dimensional, whole-atrial DF maps on which high DF (HDF) sites were ablated and resulted in significant slowing of the arrhythmia and termination of sustained AF in 87% of patients with paroxysmal AF. The response of the arrhythmia to adenosine was consistent with the mechanistic hypothesis that reentry in those HDF sites maintains AF in humans, and that reentrant drivers have different locations in paroxysmal compared with persistent AF patients.