Cell fusion has long been known to produce viable cells and to have a major role in mammalian development and differentiation. As gene expression profiles can change after cell fusion, this event must be also considered as an alternative explanation for the many cases of ‘stem cell plasticity’ that have been recently described and are promoted as a promising therapeutic strategy. Cell fusion has been demonstrated to occur in some recent studies, and the available evidence is often not inconsistent with cell fusion in others. Cell fusion itself has therapeutic potential, but low rates of spontaneous fusion and safety concerns may ultimately limit its use.