Cardiovascular diseases continue to be a leading cause of death and disability. Despite this alarming fact, there is lack of effectual treatment and the molecular mechanisms underlying these devastating diseases remain elusive. Intercalated disk (ICD) is not only essential for the integrity of cardiomyocytes to withstand the strong mechanical forces imposed by constant heart beating; it is also critical for the dissemination of the electrical signal that initiates cardiac contraction. However, relatively less is known about how ICD transmits pathophysiological signals in cardiomyocytes to modulate gene expression and cardiac function. The Xin-α and Xin-β, belongs to a family of Xin-repeat containing proteins, are primarily located at the ICD of adult cardiomyocytes. They play an important role during heart development. Interestingly, the human homologue of the mouse Xin-β gene was mapped to a locus associated with cardiomyopathy; most importantly, mutations in Xin-α and Xin-β have been found in patients with cardiomyopathy, underscoring the importance of Xin genes to cardiac disease. Our previous studies have shown that Xin-β KO mice die postnatally with severe cardiomyopathy. Here, we report that loss of Xin-β results in defect in cardiomyocyte proliferation. Unbiased transcriptome analyses reveal that gene program related to the Hippo/Yap pathway is altered, leading to the hypothesis that Xin-β regulates cardiomyocyte proliferation and cardiac function by modulating the Hippo/Yap signaling. We identify physical and genetic interaction between Xin-β and components of the Hippo/Yap pathway. We further show that the expression of Xin-β is transcriptionally regulated by Mef2a, Yap and Tead1, suggesting the presence of a Xin-β/Yap feedback regulatory network in the heart. Strikingly, cardiac-specific overexpression of Yap markedly rescues cardiac defects in Xin-β KO mice; indicating a functional and genetic interaction between Xin-β and Yap. Together, our study reveals a novel molecular mechanism by which the ICD protein Xin-β modulates important pathophysiological Hippo/Yap signals to control heart development and cardiac function. Molecules uncovered here will become candidate targets for therapeutic treatment of cardiac disease.