Loss of cardiomyocytes (CMs), which lack the innate ability to regenerate, due to ageing or pathophysiological conditions (at the. or pathophysiological conditions (at the.g. myocardial infarction or MI) can have lethal effects by hastening the progression GSS of heart failure (HF, primarily a disease of the ventricle) and/or predisposing to conduction abnormalities and arrhythmias. Current therapeutic regimes are palliative in nature, and in the case of end-stage HF, heart transplantation remains the and resort. Since this option is usually severely limited by the number of available donor organs, cell replacement therapy presents a laudable option for myocardial repair. Regrettably, however, it is usually also limited by the availability of transplantable human CMs (at the.g. human fetal CMs) due to practical and ethical considerations. As a result, transplantation of non-cardiac cells such as skeletal muscle mass myoblasts (SkMs), easy muscle mass cells and bone marrow-derived mesenchymal stem cells (MSCs) has been sought as a potentially viable option. However, the non-cardiac identity of these cell sources has offered major limitations. In the case of SkMs, their lack of electrical integration after transplantation into the myocardium has been shown to underlie the generation of malignant ventricular arrhythmias, leading to the premature termination of their clinical trials. As for bone marrow stem cells, it is usually now well established that they lack the capacity to transdifferentiate into cardiac muscle mass (Murry 2004), limiting their power for myocardial repair. Indeed, numerous cardiac and non-cardiac lineages, as well as embryonic and adult stem cell populations, have been investigated as potential sources, with their pros and negatives extensively examined elsewhere (Menasche 2003; Smits 2003; Murry 2004; Sil 2004; Kong 2010; Poon 2011). This review focuses on human (h) pluripotent stem cells (PSCs) that have been shown to generate authentic human CMs, with an emphasis on their Ca2+-handling properties. Human pluripotent stem cells C embryonic and induced pluripotent stem cells Upon fertilization of an oocyte by sperm, the resultant zygote, which possesses the total potential (i.at the. totipotency) to develop into all cell types including those necessary for embryonic development (such as extra-embryonic tissues), undergoes several rounds of cell division to become a compact Raltitrexed (Tomudex) ball of totipotent cells known as the morula. As the morula continues to grow (4 days after fertilization), its cells migrate to form a more specialized hollow, fluid-filled structure known as the blastocyst consisting of an outer cell layer, the trophectoderm, and an inner cluster of cells collectively known as the inner cell mass (ICM). While the trophectoderm is usually committed to developing into extra-embryonic structures for supporting fetal development, the ICM that retains the ability to form any cell of the body except the placental tissues (i.at the. Raltitrexed (Tomudex) pluripotency) will give rise to the embryo. Embryonic stem cells (ESCs) are isolated from the ICM. ESCs possess the ability to remain undifferentiated and propagate while maintaining their normal karyotype and pluripotency to differentiate into all the three embryonic germ layers (i.at the. endoderm, mesoderm and ectoderm) as well as their lineage derivatives including brain, blood, pancreatic, heart and other muscle mass cells. Pluripotent mammalian ESC lines were first produced from rodent blastocysts 30 years ago (Evans & Kaufman, 1981; Martin, 1981), leading to the generation of the first transgenic animal and thereby revolutionizing genetics and disease modelling; the human version was first successfully isolated about a quarter century later (Thomson 1998). As an option, direct reprogramming of adult somatic cells to become hES-like induced pluripotent stem cells (iPSCs) has been developed. Forced manifestation of Raltitrexed (Tomudex) four pluripotency genes, Oct3/4, Sox2, c-Myc, and Klf4 (Takahashi & Yamanaka, 2006; Meissner 2007; Takahashi 2007),.