Cardiomyocytes are terminally differentiated and are unable to proliferate in response to injury. Genetic modulation, cell transplantation and tissue engineering promise a revolutionary approach for myocardial regeneration and tissue repair after myocardial injury. Current data derived from animal models suggest that it may be possible to treat heart failure by inserting genetic materials or myogenic cells into injured myocardium. Success with animal models has raised the hope for new treatment after heart attacks and could prove an alternative to transplantation, particularly in elderly patients for whom there is often a lack of donor hearts. This exciting research, however, still faces significant difficulties before it can develop into a clinical therapeutic tool and many challenges need to be overcome before cell transplantation, gene therapy and tissue engineering can be considered efficient, therapeutic strategies for myocardial regeneration.