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 chronically infarcted heart through regeneration of fibrotic scars. Because the engrafted myoblasts do not connect with the host cardiomyocytes, it is increasingly considered that the functional benefits of myogenic cell transplantation are more related to limitation of adverse post-infarction remodelling and/or paracrine signalling on recipient tissue rather than to a synchronous contribution of the graft to the heart's systolic function. The initial clinical studies of intra-operative myoblast transplantation have primarily documented the feasibility of the procedure and unravelled a potential pro-arrhythmic risk that needs to be further characterized. It is now critical to assess whether the functional benefits observed in the laboratory setting translate into meaningful improvements in local and global contractility and ultimate patient outcomes. The results of ongoing randomized trials should soon help clarifying this efficacy issue. In parallel, experimental studies need to be actively pursued to address some remaining key issues including the means of optimizing myoblast delivery, engraftment and survival, and the development of a second-line generation of cells featuring the potential of a true electromechanical integration within the recipient myocardium. © The European Society of Cardiology 2006. All rights reserved.