Although the problem of atrial fibrillation is now widely appreciated, the fundamental mechanisms that lead to arrhythmia onset and persistence have been difficult to elucidate. As a result, available pharmacologic therapies have focused more on modifying ion channel activity than on the underlying mechanisms. Recent studies suggest an important role for alterations in autonomic regulation, neurohormonal activation, and a systemic inflammatory state in the genesis and persistence of atrial fibrillation. The relative contributions of these distinct pathways to atrial fibrillation likely vary from patient to patient, and within a patient, as a function of age. Tailored therapies, together with patient-specific ablative interventions, may increase the success with which atrial fibrillation is treated and minimize the occurrence of life-threatening thromboembolic complications.