Cell-cell fusion is a natural process that occurs not only during development, but as has emerged over the last few years, also with an important role in tissue regeneration. Interestingly, in-vitro studies have revealed that after fusion of two different cell types, the developmental potential of these cells can change. This suggests that the mechanisms by which cells differentiate during development to acquire their identities is not irreversible, as was considered until a few years ago. To date, it is well established that the fate of a cell can be changed by a process known as reprogramming. This mainly occurs in two different ways: the differentiated state of a cell can be reversed back into a pluripotent state (pluripotent reprogramming), or it can be switched directly to a different differentiated state (lineage reprogramming). In both cases, these possibilities of obtaining sources of autologous somatic cells to maintain, replace or rescue different tissues has provided new and fundamental insights in the stem-cell-therapy field. Most interestingly, the concept that cell reprogramming can also occur in vivo by spontaneous cell fusion events is also emerging, which suggests that this mechanism can be implicated not only in cellular plasticity, but also in tissue regeneration. In this chapter, we will summarize the present knowledge of the molecular mechanisms that mediate the restoration of pluripotency in vitro through cell fusion, as well as the studies carried out over the last 3 decades on lineage reprogramming, both in vitro and in vivo. How the outcome of these studies relate to regenerative medicine applications will also be discussed.