Over the past decade, the concept that the heart could undergo cardiac regeneration has rapidly evolved. Studies have indicated that numerous sites in the body harbor stem or progenitor cells, prompting clinical trials of these potential therapeutic cell-based approaches. Most notable are the series of trials utilizing either skeletal myoblasts or autologous whole bone marrow. More recently the quest has focused on specific bone marrow constituents, most notably the mesenchymal stem cell, which has several unique advantages including immunoprivilege, immunosuppression, and the ability to home to areas of tissue injury. Most recently, cells have been identified within the heart itself that are capable of self-replication and differentiation. The discovery of cardiac stem cells offers not only a potential therapeutic approach but also provides a plausible target for endogenous activation as a therapeutic strategy. Together the new insights obtained from studies of cell-based cardiac therapy have ushered in new biological paradigms and enormous potential for novel therapeutic strategies for cardiac disease.