Clinical and research data indicate that active and passive changes in the mechanical environment of the heart are capable of influencing both the initiation and the spread of cardiac excitation via pathways that are intrinsic to the heart. This direction of the cross-talk between cardiac electrical and mechanical activity is referred to as mechano-electric feedback (MEF). MEF is thought to be involved in the adjustment of heart rate to changes in mechanical load and would help to explain the precise beat-to-beat regulation of cardiac performance as it occurs even in the recently transplanted (and, thus, denervated) heart. Furthermore, there is clinical evidence that MEF may be involved in mechanical initiation of arrhythmias and fibrillation, as well as in the re-setting of disturbed heart rhythm by 'mechanical' first aid procedures. This review will outline the clinical relevance of cardiac MEF, describe cellular correlates to the responses observed in situ, and discuss the role that quantitative mathematical models may play in identifying the involvement of cardiac MEF in the regulation of heart rate and rhythm.