The biological phenomenon of cell fusion is involved in several physiological (fertilization, tissue regeneration) and pathophysiological (viral infection, cancer) processes. Particularly in the tumor context, cell fusion has been associated with a progression of this disease since hybrid cells derived from fusion events between tumor cells and normal cells, such as macrophages and adult stem cells, exhibited novel properties. These included an enhanced metastatogenic capacity, an increased proliferation, an increased resistance to undergo apoptosis or an increased drug resistance. But how the high phenotypic diversity of tumor hybrid cells is achieved? Cell fusion is a strong inducer of aneuploidy and genomic instability in tumor hybrid cells. Heterokaryon-to-synkaryon transition, representing the mechanism of nuclear fusion, is associated with a loss and re-sorting of chromosomes in a random manner, resulting in unique hybrid cells, whereby the degree of the aneuploidy/ genomic instability is further enhanced during ongoing rounds of cell divisions. The random nature of cell fusion tumor hybrid cells may originate already exhibiting an increased drug resistance, e.g., due to up-regulation of drug resistance related proteins. However, due to the aneuploidy/ genomic instability the hybrid cells may originate exhibiting an enhanced adaptation capacity, enabling these cells to withstand cellular stresses.