The highly organized transverse (T)-tubule network is critical for rapid electric excitation and synchronous triggering of sarcoplasmic reticulum (SR) Ca2+ release, and, therefore, coordinated and efficient excitation-contraction coupling function in working ventricular myocytes. Because of the critical roles played by T-tubules, T-tubule architecture has recently become an area of considerable research interest in the cardiovascular field. Early studies from us and others have shown that the regularly arrayed T-tubule system undergoes disruptive remodeling, leading to aberrant intracellular Ca2+ release and compromised myocyte contractility, in failing myocytes from animal models and human patients. Recently, using in situ confocal imaging technique, we showed that in a pressure overload rat cardiomyopathy model the remodeling of T-tubules starts much earlier in the disease spectrum, even prior to echocardiographically-detectable left ventricular (LV) systolic dysfunction. The T-tubule system in the LV undergoes progressive deterioration from compensated hypertrophy through early heart failure to advanced heart failure. Moreover, the integrity of T-tubule system highly correlates with cardiac ejection fraction of diseased hearts, indicating T-tubule integrity is a crucial determinant of cardiac function, and that maladaptive T-tubule remodeling is a causal event that drives the transition from compensated hypertrophy to heart failure. In more recent work, we have dissected the molecular mechanisms underlying T-tubule remodeling in heart disease, in particular the importance of junctophilin-2 (JP2), a structural protein spanning T-tubules and the SR membrane. JP2 is severely downregulated in multiple heart failure models as well as in failing human hearts. Furthermore, loss of JP expression correlates with the extent of T-tubule damage. In cultured myocytes, knockdown of JP2 using lentivirus containing a JP2 shRNA caused T-tubule disorganization. Transgenic expression of a JP2 shRNA in mice induced T-tubule structural damage, dyssynchronous and blunted Ca2+ release, and acute heart failure. These data provide compelling evidence that JP2 is a key mediator of myocyte T-tubule remodeling in cardiac disease.