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The specific transformative steps that occur from the multipotent through the mature cardiomyocyte state are determined in large part by changes in gene expression. The exact differentiation and developmental programs are tightly regulated in a step-wise systematic fashion based on the influence of specific instigating and signaling factors. Crucial to the observed cell behavior and tissue specific phenotypic differences are alterations in the organization, translocation and expression of nuclear proteins during differentiation. The cardiomyogenic differentiation of Mesenchymal Stem Cells (MSCs) remains a precarious process. Transplanted MSCs must respond to endogenous signaling molecules involved in early embryonic cardiomyogenesis by activating the specific gene regulatory network required for successful cardiomyogenesis and transdifferentiation. To do that, transplanted MSCs would have to be genuinely reprogrammed genetically to become functional cardiac myocytes. A consideration of recent experimental findings suggests that Bone morphogenic protein (BMP-2/4), insulin-like growth factor (IGF-1) and fibroblast growth factor (FGF-2) in combination is a potent inducer of MSC cardiomyogenesis. The development of an optimum and reliable in vitro culture milieu for directing their cardiomyogenesis will provide an indispensable model system for molecular studies and genetic manipulation.