The expression and function of numerous cardiac ion channels change with development and disease. Whereas multiple regulatory processes and molecular mechanisms are certainly involved, one factor, sympathetic innervation, contributes to many of the developmental changes and is suggested to play a role in pathology. The onset of cardiac sympathetic innervation of the mammalian ventricle during early post-natal life has been associated with functional alterations in several ionic currents, including Na(+), L-type Ca(2+), pacemaker, inward rectifier and transient outward K(+) currents. The neural signaling molecule is not the same in each case, with evidence pointing to contributions from sustained activation of myocardial neuropeptide Y receptors, alpha-adrenergic receptors and beta-adrenergic receptors, as well as additional, but as yet unidentified, targets. Knowledge of the mechanisms by which innervation regulates ion channel expression and function during normal development may aid efforts to reverse remodel the diseased heart and to target pharmacologic agents to remodeled channels.