The heart is a paradigm of organ provided with unique three-dimensional tissue architecture that is molded during complex organogenesis processes and is required for the heart's physiological function. The cardiac stroma plays a critical role in the formation and maintenance of the normal heart architecture, as well as of its changes occurring in cardiac diseases. Recent studies have shown that the cardiac stroma, including the epicardium, myocardial interstitium, and endocardium, contains typical telocytes: these cells establish complex spatial relationships with cardiomyocytes and cardiac stem cells suggestive for a regulatory role over three-dimensional organization of heart tissues. Telocytes appear early during prenatal heart development and represent a major stromal cell population in the adult heart. Numerous studies have highlighted that telocytes, through juxtacrine and paracrine mechanisms, can behave as nursing cells for cardiac muscle stem cells modulating their growth and differentiation. On these grounds, a possible role of telocytes in cardiac regeneration can be postulated: this hypothesis is supported by recent experimental findings that reduction of cardiac telocytes due to hypoxia may concur to explain the negligible regenerative ability of the post-infarcted heart, while grafting of telocytes in the injured myocardium improves adverse heart remodeling. The increasing knowledge on the properties of cardiac telocytes is orienting the research toward their role as key regulators of the three-dimensional architecture of the heart and new promising targets for cardiac regenerative medicine.