Cell fusion, which occurs in both tissue injury and cancer, inevitably results in polyploidization. While polyploid cells often fail to proliferate, polyploidization does not invariably lead to growth arrest, and polyploid cells can resume proliferation under certain conditions. Notably, the proliferation of polyploid cells is frequently accompanied by genomic instability, including replication stress and chromosomal instability. Furthermore, some polyploid cells have the capacity to reduce their ploidy and revert to a diploid state. Growing evidence indicates that such genomic instability and ploidy fluctuations act as driving forces of clonal evolution. This chapter discusses ploidy changes and genomic instability arising from cell fusion and examines how these alterations influence cellular behavior.