Cell fusion is a natural process implicated in normal development, immune response, tissue formation, and with a prominent role in stem cell plasticity. The discovery that bone marrow stem cells fuse with several cell types, under normal condition or after an injury, introduces new possibilities in regenerative medicine and genetic repair. Cell fusion has been shown to be implicated in regeneration, and the complementation of recessive mutations affecting the liver, brain, muscle, lung and gut, under appropriate conditions. However, we should be cautious and better understand the mechanisms that govern cell fusion during regeneration before to consider it as clinically relevant. In this chapter, we will present the current evidences about the role of cell fusion in tissue regeneration and its future potential as therapy. Cell fusion is an exciting and promising research field. In addition, we will review the challenges that should face the fusion process to become therapeutically effective and safe.