Stem cell therapy using bone marrow derived or mesenchymal stem cells has become a popular option for cardiovascular disease treatment, however the administration of embryonic stem cells has been mostly experimental. Remarkably, most of these ongoing clinical trials involve adult patients, but little is known regarding the safety and efficacy of stem cell therapy in newborns and children battling congenital heart diseases. Furthermore, cell delivery methods involve the administration of stem cells without pre-differentiation, and without consideration for the consequent process of cardiac development. Interestingly, in-vitro studies have demonstrated that the differentiation of embryonic stem cells into cardiomyocytes imitates the stages of cardiogenesis. Wnt signaling plays a profound role during the earliest stages of cardiogenesis and cardiac differentiation. In fact inappropriate Wnt signaling is associated with numerous cardiac disorders especially congenital heart disease. Furthermore, cell-extracellular matrix interactions were shown to be critical for stem cell differentiation and adequate cardiogenesis. Since extracellular matrix molecules are fundamental for maintenance and repair during heart disease and congenital heart disease, they may offer a novel approach for therapy. Herein we aim to review the critical role of Wnt signaling, as well as the profound importance of cell extracellular matrix interaction, during cardiogenesis. Both of these processes are crucial for precise stem cell differentiation into cardiomyocytes and developing efficacious regenerative therapy for congenital heart disease. Copyright © 2019 Elsevier Inc. All rights reserved.