After a decade of experimental work, skeletal myoblast transplantation has now entered the clinical arena as a potentially new means of improving the function of the failing heart. Because of the apparent lack of connections between the engrafted myoblasts and the host cardiomyocytes, it is likely that the functional benefits of myogenic cell transplantation are more related to limitation of adverse post-infarction remodelling and/or paracrine effects on recipient tissue rather than to a synchronous contribution of the graft to systolic pump function. As the initial clinical studies have primarily documented the feasibility of the procedure, it is now critical to assess whether the functional benefits observed in the laboratory setting translate into meaningful improvements in cardiac contractility and ultimate patient outcomes. Only randomised trials will allow us to satisfactorily address efficacy. These trials should also clarify the potentially pro-arrhythmic risk of myoblast engraftment, which might be related to the heterogeneous electrical properties between donor and recipient cells. In parallel, additional experimental studies are still warranted to address some key issues including the means of optimising post-transplantation myoblast survival, the development of less invasive cell transfer delivery technologies, the role of myoblast transplantation in non-ischemic heart failure settings and the comparative effects of skeletal myoblasts compared with other potential forms of cell therapy such as bone marrow-derived and embryonic stem cells. © 2005 Lippincott Williams & Wilkins.