The use of cell fusion to study exchange of information at the molecular level between the nucleus and the cytoplasm of cells during regulation of gene expression was pioneered by Harris and Ringertz more than three decades ago. The ability to make heterokaryons with cells from different species or genetic strains is especially useful because genetic differences in gene products allow the origin of trans-acting regulatory factors to be determined. Heterokaryons between adult nucleated erythroid cells of one species and embryonic/larval nucleated erythroid cells of another species, for example, show cross-induction between the two types of nuclei, resulting in reprogramming of the adult nucleus to embryonic/larval globin gene expression and/or reprogramming of the embryonic/larval cell nucleus to adult globin expression. These experiments provided definitive evidence that developmental program switching is mediated by trans-acting factors. Other possible uses of this cell fusion protocol in stem cell biology and transplantation of genetically engineered cells for tissue regeneration are briefly discussed.