The study and use of cell fusion has been an invaluable tool in somatic cell genetics, and it has highlighted the complexity of the mechanisms that regulate the maintenance of the determined and differentiated states. Cell fusion recently surfaced as an issue in analyzing data from experiments designed to demonstrate the pluripotency of various adult stem cells. The phenomenon of spontaneous cell fusion has been known for a considerable time, and experimentally induced cell fusion has been widely used for both genetic analysis and studies of the differentiated and determined states. The ability of pluripotent stem cells to reprogram somatic nuclei to a primitive, pluripotent state increases the potential of achieving somatic cell reprogramming in an efficient manner for therapeutic purposes without resorting to nuclear transfer to oocytes, so-called therapeutic cloning. The phenomenon of spontaneous fusion is also an issue to be addressed in the analysis of any claims for plasticity of otherwise lineage-restricted, adult stem cells. It is shown that specific drug selection techniques could be used to isolate hybrid cells and the hypoxanthine-aminopterin-thymidine selection system to eliminate parental cells separately deficient in hypoxanthine phosphoribosyl transferase and thymidine kinase. Genetic complementation resulting in expression of both enzymes allowed for survival of the hybrids. By correlating the expression of human traits in such hybrids with the retention of particular human chromosomes, individual human genes could be located on specific chromosomes or even parts of chromosomes.