Since the birth of Dolly, the first mammal produced from somatic cell nuclear transfer (SCNT), little progress has been made in the efficiency of cloning. Overall, about 0.5–2% of the embryos reconstructed by SCNT develop to term after transfer of reconstructed embryos to recipient females. In PNAS, Matoba et al.(1) report significant improvement in cloning efficiency by manipulation of the level of the Xist transcript. SCNT involves replacement of the metaphase II chromosomes of a mature oocyte with the nucleus of a differentiated cell. Without any additional intervention, the nuclear envelop breaks down and the chromatin condenses into a structure that is similar to the recently removed metaphase II chromosomes. A variety of methods can be used to mimic the early events of fertilization such that the oocyte is activated to begin the embryonic developmental program in the absence of fertilization. However, the transferred nucleus was actively participating in a somatic developmental program at the time that it was harvested or transferred. To begin, the newly initiated embryonic developmental program requires an event similar to a computer reboot—the somatic program must be restarted as an embryonic program. In contrast to the computer analogy, factors that affect cell identity or result from the cell’s history can still associate with the genome such that genes that are not normally expressed in early development can be inappropriately expressed in the reconstructed embryo (2). Similarly, because the somatic nucleus does not pass through a germ cell developmental program in which epigenetic modifications are normally reset, the epigenetic modifications that have occurred over the history of the somatic nucleus are not erased and reestablished (Fig. 1). As a result of retained transcription factors and epigenetic marks, the transferred nucleus must be actively reprogrammed amid mixed developmental signals. Because the oocyte volume is large compared with most somatic cells or isolated nuclei, most somatic transcription factors are likely severely diluted at nuclear transfer or during subsequent cell divisions. However, because maintenance of epigenetic marks is not well-described, it is unclear how modified histones and DNA methylation are reset or reprogrammed during early development of reconstructed embryos. In the systems that are most studied (3, 4), it seems that placental inefficiencies are a major cause of embryonic loss in cloned mammals. However, those embryos that develop to term can still display abnormalities. Most of the abnormalities observed in clones are reminiscent of conditions observed in humans that are associated with altered parent of origin genomic imprinting. Although there may be many factors that contribute to a lack of viability in SCNT embryos, it seems that genomic imprinting is involved. Xist is an X-linked gene that produces a noncoding RNA, and it is one of the first imprinted genes to be expressed in the early embryo with expression beginning at zygotic genome activation (5). Although Xist is known to be involved in X-chromosome inactivation in females, the function of Xist RNA is not fully understood (6). Many genes are aberrantly expressed in cloned embryos (2, 7), and Xist is among these genes (8). Using nuclear donor cells that harbor a defective Xist gene, it has been shown that, in the absence of Xist expression, several aberrantly expressed genes approach normal expression patterns in cloned mouse embryos (9). In PNAS, the work by Matoba et al.(1) extends this line of investigation by a demonstration that an siRNA approach can temporarily reduce Xist RNA in the early preimplantation embryo …