Gene manipulation has been the constant pursuit of geneticists since the end of the 19th century. Although initially started as a means to improve and select for the good qualities of species, the potential of gene manipulation was not realized until random mutagenesis screens were devised in bacteriophages and fruit flies in order to score the resultant phenotypes. Several advances in gene cloning, chromosomal mapping and DNA sequencing and a wealth of breeding data on various species have heralded a new era of introducing foreign DNA into chromosomes of the host species. Moreover, micromanipulation of one-cell mouse embryos is considered technically relatively easy when compared to that in other species. Our group has generated several lines of transgenic mice that phenocopy many human reproductive diseases. In the following sections, we will discuss general principles of transgenic mouse technology and provide detailed methods in later sections. There are two basic technical approaches to produce genetically modified mice. This method creates a transgenic mouse and is used to insert new genetic information into the mouse genome or to over-express endogenous genes. The second approach, pioneered by Oliver Smithies and Mario Capecchi, involves modifying embryonic stem cells with a DNA construct containing DNA sequences homologous to the target gene.