The central tenet of stem cell biology is that within tissues there reside stem cells with the capacity for both self-renewal and terminal differentiation to the multiple lineages of that tissue. Over the last few years, numerous studies have challenged this paradigm by showing that tissue stem cells can differentiate to unexpected cell lineages, suggesting an enormous plasticity of differentiation. The hematopoietic stem cell, which resides within bone marrow and gives rise to all blood cells, has been the focal point of these efforts. However, recent studies have disputed the notion of hematopoietic stem cell plasticity. In truth, stem cell plasticity, strictly defined, has yet to be rigorously proven. Both animal models to carefully address outstanding issues and pilot clinical trials to explore the therapeutic potential will be key elements to advance science for the benefit of patients.