Despite the advancement of medical treatment, heart failure remains one of the major factors contributing to mortality in Western nations. Changes in calcium (Ca__) regulation contribute to loss of contractility and have been determined as a primary cause of heart failure. New therapeutic strategies to treat heart failure require understanding how Ca__ signaling genes interact with each other. The three primary genes involved in this regulation are ryanodine receptors (RyRs), which release calcium from sarcoplasmic reticulum (SR); the SR calcium ATPase (SERCA) and sarcolemmal sodium-calcium exchanger (NCX) which causes the restoration of low resting cytosolic calcium. In this study, I have conducted studies to determine how down-regulation of RyR2 affects NCX and SERCA expression, and similarly how down-regulation of NCX in turn affects the expression of RyR2 and SERCA. Furthermore, I assess contractility by tracking internal cardiomyocyte changes during each contraction and analyze Ca__ transient magnitudes and time courses using time-lapse fluorescence microscopy. My results show that when RyR2 is down-regulated, the expression of SERCA is significantly down-regulated and the expression of NCX is up-regulated. Meanwhile the amplitude of calcium transient are decreased and contractile parameters were impaired. In contrast, the depletion of NCX gene expression was accompanied by a significant increase of SERCA gene expression while Ca__ homeostasis and contractile function are not significantly affected. This study supports the role for RyR2 as the main regulator for cardiac contractility and also affirms the compensatory function of SERCA and NCX in neonatal cardiomyocytes. The results demonstrate how changes in intracellular calcium regulated by RyR2, SERCA and NCX control contractility in the cardiomyocyte.