The heart is extensively innervated and its performance is tightly controlled by the nervous system. Cardiac innervation density varies in diseased hearts leading to unbalanced neural activation and lethal arrhythmia. Diabetic sensory neuropathy causes silent myocardial ischemia, characterized by loss of pain perception during myocardial ischemia, which is a major cause of sudden cardiac death in diabetes mellitus (DM). Despite its clinical importance, the mechanisms underlying the control and regulation of cardiac innervation remain poorly understood. We found that cardiac innervation is determined by the balance between neural chemoattractants and chemorepellents within the heart. Nerve growth factor (NGF), a potent chemoattractant, is induced by endothelin-1 upregulation during development and is highly expressed in cardiomyocytes. By comparison, Sema3a, a neural chemorepellent, is highly expressed in the subendocardium of early stage embryos, and is suppressed during development. The balance of expression between NGF and Seme3a leads to epicardial-to-endocardial transmural sympathetic innervation patterning. We also found that downregulation of cardiac NGF leads to diabetic neuropathy, and that NGF supplementation rescues silent myocardial ischemia in DM. Cardiac innervation patterning is disrupted in Sema3a-deficient and Sema3aoverexpressing mice, leading to sudden death or lethal arrhythmias. The present review focuses on the regulatory mechanisms underlying cardiac innervation and the critical role of these processes in cardiac performance.