The rate and force of contraction of the heart are precisely controlled by compartmentalized regulation of cardiac ion channels which determine electrical activities. It is known that modulation of cardiac ion channels, which is caused by drug administration, sympathetic nervous system stimulation and gender difference, can increase risks of lethal arrhythmias in carriers of inherited disease mutations. These modulations are thought to also be involved in common cardiac arrhythmias. Because many signaling molecules are localized within single cells, an understanding of the molecular basis of compartmentalized regulation of cardiac channels is a key for understanding and treating the lethal arrhythmias. In this review, I will discuss molecular mechanisms of compartmentalized regulation of cardiac ion channels via drugs, cAMP and sex hormones.