Abstract—Stem cells are being investigated for their potential use in regenerative medicine. A series of remarkable studies suggested that adult stem cells undergo novel patterns of development by a process referred to as transdifferentiation or plasticity. These observations fueled an exciting period of discovery and high expectations followed by controversy that emerged from data suggesting cell-cell fusion as an alternate interpretation for transdifferentiation. However, data supporting stem cell plasticity are extensive and cannot be easily dismissed. Myocardial regeneration is perhaps the most widely studied and debated example of stem cell plasticity. Early reports from animal and clinical investigations disagree on the extent of myocardial renewal in adults, but evidence indicates that cardiomyocytes are generated in what was previously considered a postmitotic organ. On the basis of postmortem microscopic analysis, it is proposed that renewal is achieved by stem cells that infiltrate normal and infarcted myocardium. To further understand the role of stem cells in regeneration, it is incumbent on us to develop instrumentation and technologies to monitor myocardial repair over time in large animal models. This may be achieved by tracking labeled stem cells as they migrate into myocardial infarctions. In addition, we must begin to identify the environmental cues that are needed for stem cell trafficking and we must define the genetic and cellular mechanisms that initiate transdifferentiation. Only then will we be able to regulate this process and begin to realize the full potential of stem cells in regenerative medicine.