Fifty years after Briggs and King first succeeded in obtaining normal tadpoles from transplanted embryo nuclei in vertebrates, two general principles have emerged from work in amphibia and mammals. One is the conservation of the genome during cell differentiation. A small percentage of adult or differentiated cells have totipotent nuclei, and a much higher percentage of cells committed to one pathway of cell differentiation have multipotent nuclei. The other is the remarkable reprogramming capacity of cell, and especially egg, cytoplasm. The eventual identification of reprogramming molecules and mechanisms could facilitate a route toward cell replacement therapy in humans.