Cloning of mammals by nuclear transfer can lead to the birth of healthy adult animals but more often compromises the development of the reconstructed embryos. A high incidence of fetal and postnatal losses has been observed in several species, revealing the existence of long-lasting effects induced by the nuclear transfer procedures. Remodeling of donor chromatin by the recipient cytoplasm after nuclear transfer is frequently associated with the deregulation of specific genes, and recent observations point to the potential importance of time-dependent DNA methylation events in the occurrence of these alterations. Screening strategies to design nuclear transfer procedures that would mimic the epigenetic remodeling occurring in normal embryos are being designed, and improvement in the efficiency of procedures could imply a pre-conditioning of donor cells. Early mammalian development appears to be rather tolerant to epigenetic abnormalities, raising the possibility that even a fully functional reprogrammed genome may have been subjected to some epigenetic alterations. Bringing nuclear transfer to routine practice requires greater knowledge and understanding of the basic biological processes underlying epigenetic controls of nuclear activities. An important issue at present is to limit the production of those aberrant phenotypes that may result in significant insult to the nature and welfare of animals.