Repair of diseased or injured myocardium by cell-based therapies is likely to require a multi-pronged approach. New myocytes will need to be generated, integrated with existing myocardial tissue, and perfused with a newly acquired vascular system. There are many potential avenues to achieve this goal, and optimizing repair is likely to require a synthetic therapeutic approach. In this review, we discuss several issues to be considered in cell-based cardiac repair, some progress which has been made toward this goal, and future directions.