Embryonic stem cells (ESCs) are a pluripotent cell type that may be considered for treatments in cell replacement therapies, such as for cardiovascular disease. The general premise is that ESCs may be differentiated in vitro into embryonic stem cell-derived cardiomyocytes (ESCMs). These ESCMs may then be directly injected into the damaged myocardium, which would facilitate the regeneration of the tissue. Indeed, multiple animal studies have shown this methodology to be promising. However, before these cells can be taken to clinical trials, several obstacles need to be overcome, including heterogeneity, which is a potential problem during ESC maintenance and differentiation. This review focuses on signaling pathways, such a Wnt/beta-catenin and bone morphogenic protein, (BMP), which influence cardiomyocyte specification from ESCs. By modifying signaling pathways in a temporal manner, we may be able to promote ESCM differentiation and reduce heterogeneity. Furthermore, we have recently found that by modifying the fibroblast growth factor receptor (FGFR)-Grb2-Ras-Mek-Erk pathway, we can effectively reduce the heterogeneity found during normal ESC maintenance. Such approaches will be beneficial in promoting the possibility of using ESCMs in transplantation therapies.