Abstract: Acquired epigenetic modifications, such as DNA methylation or stable chromatin structures, are not normally thought to be inherited through the germline to future generations in mammals [1Jablonka E Lamb MJ Epigenetic Inheritance and Evolution, The Lamarckian Dimension. Oxford University Press, Oxford1995Google Scholar, 2Landman OE The inheritance of acquired characteristics.Annu Rev Genet. 1991; 25 (92255249): 1-20Crossref PubMed Scopus (68) Google Scholar]. Studies in the mouse have shown that specific manipulations of early embryos, such as nuclear transplantation, can result in altered patterns of gene expression and induce phenotypic alterations at later stages of development [3Latham KE Solter D Effect of egg composition on the developmental capacity of androgenetic mouse embryos.Development. 1991; 113 (92146267): 561-568PubMed Google Scholar, 4Reik W Roemer I Barton SC Surani MA Howlett SK Klose J Adult phenotype in the mouse can be affected by epigenetic events in the early embryos.Development. 1993; 119 (94244485): 933-942PubMed Google Scholar, 5Latham KE Strain specific differences in mouse oocytes and their contributions to epigenetic inheritance.Development. 1994; 120 (95121200): 3419-3426PubMed Google Scholar]. These effects are consistent with acquired epigenetic modifications that are somatically heritable, such as DNA methylation. Repression and DNA methylation of genes encoding major urinary proteins, repression of the gene encoding olfactory marker protein, and reduced body weight can be experimentally induced by nuclear transplantation in early embryos [[4]Reik W Roemer I Barton SC Surani MA Howlett SK Klose J Adult phenotype in the mouse can be affected by epigenetic events in the early embryos.Development. 1993; 119 (94244485): 933-942PubMed Google Scholar]. Strikingly, we now report that these acquired phenotypes are transmitted to most of the offspring of manipulated parent mice. This is the first demonstration of epigenetic inheritance of specific alterations of gene expression through the germline. These observations establish a mammalian model for transgenerational effects that are important for humal health, and also raise the question of the evolutionary importance of epigenetic inheritance.