Pluripotent stem cells hold great potential for future regenerative therapies as well as for disease modeling of both common and rare diseases alike. Human embryonic stem cells (hESC) and induced pluripotent stem cells (iPSC) are cell types which are currently being utilized for research purposes. Both have the capability to produce cells of the three germ layers (endoderm, mesoderm, ectoderm), and have been practically shown to differentiate to cells of the three germ layers. The major aim of this study was to utilize pluripotent stem cells to investigate cardiogenesis, both under normal conditions and in a model of cardiac disease, namely, Down syndrome. Furthermore, due to the significant differences reported between hESC and iPSC, we aimed to investigate hESC and iPSC from the same genetic background in order to understand if genetic differences impact the divergent characteristics of iPSC vs. hESC, a goal that, to date, had not been achieved.