This is a personal historical account of events leading from the earliest success in vertebrate nuclear transfer to the current hope that nuclear reprogramming may facilitate cell replacement therapy. Early morphological evidence in Amphibia for the toti- or multipotentiality of some nuclei from differentiated cells first established the principle of the conservation of the genome during cell differentiation. Molecular markers show that many somatic cell nuclei are reprogrammed to an embryonic pattern of gene expression soon after nuclear transplantation to eggs. The germinal vesicles of oocytes in first meiotic prophase have a direct reprogramming activity on mammalian as well as amphibian nuclei and offer a route to identify nuclear reprogramming molecules. Amphibian eggs and oocytes have a truly remarkable ability to transcribe genes as DNA or nuclei, to translate mRNA, and to modify or localize proteins injected into them. The development of nuclear transplant embryos depends on the ability of cells to interpret small concentration changes of signal factors in the community effect and in morphogen gradients. Many difficulties in a career can be overcome by analyzing in increasing depth the same fundamentally interesting and important problem.