The limited regenerative potential of the heart via cell proliferation or stem cell recruitment isinsufficient to compensate for tissue loss after an acute myocardial infarction [1], [2].Consequently, the increased workload placed on the surviving myocardium often leads to heartfailure. Approximately 865,000 Americans per year suffer a myocardial infarction and nearly4.9 million are afflicted with heart failure, demonstrating the vital need for new and moreefficient therapies [ 3]. More than a decade ago, the transplantation of exogenous cells into theheart had been proposed as a method to augment compromised heart function in these diseases[2], [4]. Nowadays, the use of stem cells to rebuild a damaged heart has become a mainstreamexperimental concept in cardiac research. Moreover, the severity of heart disease and theincreasing numbers of heart failure patients have prompted attempts to implement the stemcell therapies in clinical practice. While the number of enrolled patients in clinical studies isgrowing, our understanding of the potential role of transplanted cells in cardiac repair is limited.The main questions to be answered are: Which heart disease and when should it be treated?Which cell type or combination of cell types will be the most beneficial, safe, and yield long-lasting improvement of heart function? How should these cells be delivered? What are themechanisms by which transplanted cells affect heart function, and how can this knowledge beused to promote the development of new methods for tissue repair and regeneration?Despite a number of unoptimized variables, initial clinical attempts using autologous skeletalmyoblasts [ 5] and bone marrow-derived stem cells [ 6] have demonstrated slight but significantimprovements in heart function, most likely due to the paracrine action of implanted cells andincreased vascularization of the infarct area. However, the latest results of double-blindrandomized placebo-controlled trials have been less encouraging [7]–[10]. Some of the mainhurdles have been recognized, including low retention and survival of implanted cells, as wellas limited cardiogenic differentiation and functional integration of delivered cells within thehost heart tissue. In particular, suboptimal methods for cell delivery into the heart have beenshown to result in uncontrolled cell loss (even >90%) from the injection site and largevariability of the resulting graft size [ 2]. The mixing of bioactive hydrogels with injected cellsand subsequent cell/hydrogel polymerization in situ can be used to minimize cell loss [11],[12]. However, even if a high number of cells are efficiently retained at the injection site, theirsurvival within the harsh infarct environment is not guaranteed and higher cell densities maylead to even higher cell mortality. Currently ∼90% of successfully delivered cells are shownto die within the first week after injection [2]. Heat shock treatment prior to cell implantation[13] as well as exogenous delivery of anti-apoptotic and angiogenic factors [ 14]–[16] or theiroverexpression in implanted cells [ 17], [18] are being explored in an attempt to overcome thisproblem.Nonetheless, the source of optimal donor cells for heart repair remains the most important andmost studied area in this rapidly growing field. Interestingly, a large number of donor cell typesin different animal studies have been shown to exert some functional benefit upon implantationin the heart (at least over a relatively short period after implantation). Ideally, the implantedcells should be nontumorogenic and nonimmunogenic, proliferate rapidly and abundantly invitro, and structurally and functionally integrate in sufficient numbers with host