Chromosome loss in early human embryos is thought to cause a large proportion of spontaneous abortions; when it occurs in specific cell lineages in older embryos or adults, it can result in neoplasia. Although early embryonic chromosome loss can be modelled by breeding mice carrying robertsonian translocation chromosomes, there is currently no method for producing mice with tissue-specific monosomies. Here we demonstrate that DNA recombination mediated by the site-specific recombinase Cre causes loss of a chromosome carrying loxP sites (Cre recognition sites) in an inverted orientation. Thus, when male mice carrying a Y-linked transgene containing inverted loxP sites are mated with females carrying a cre gene that is obiquitously expressed in the early embryo, almost all their XY progeny lose the Y chromosome early in embryogenesis and develop as XO females. Because inverted loxP sites can be targetted to any mouse chromosome and mice can be produced that express cre in specific cell lineages, these data suggest a method for engineering tissue-specific loss of particular chromosomes to provide mouse models for human diseases caused by or associated with specific monosomies.