Cardiac control is mediated via nested-feedback reflex control networks involving the intrinsic cardiac ganglia, intra-thoracic extra-cardiac ganglia, spinal cord, brainstem, and higher centers. This control system is optimized to respond to normal physiologic stressors; however, it can be catastrophically disrupted by pathologic events such as myocardial ischemia. In fact, it is now recognized that cardiac disease progression reflects the dynamic interplay between adverse remodeling of the cardiac substrate coupled with autonomic dysregulation. With advances in understanding of this network dynamic in normal and pathologic states, neuroscience-based neuromodulation therapies can be devised for the management of acute and chronic cardiac pathologies.