The concept of mechano-electrical feedback was derived from the observation that a short stretch applied to the beating heart can invoke an electrical response in the form of an afterdepolarization or a premature ventricular beat. More recent work has identified stretch-activated channels whose specific inhibition might help to treat atrial fibrillation in the near future. But the interaction between electrical and mechanical function of the heart is a continuum from short-term (within milliseconds) to long-term (within weeks or months) effects. The long-term effects of pressure overload have been well-described on the molecular and cellular level, and substances that interact with these processes are used in clinical routine in the care of patients with cardiac hypertrophy and heart failure. These treatments help to prevent lethal arrhythmias (sudden death) and potentially atrial fibrillation. The intermediate interaction between mechanical and electrical function of the heart is less well-understood. Several recently identified regulatory mechanisms may provide novel antiarrhythmic targets associated with the “intermediate” response of the myocardium to stretch.