Mice are increasingly employed for molecular analysis of brain function because mice, unlike rats, permit the targeted modification of genes resident in the mouse genome. Additive transgenesis, the addition of new gene combinations to the genome, was also first developed for the mouse, although the technical obstacles to additive transgenesis in laboratory rats have now been overcome (see the presentation by Dr. John Mullins). The talk is intended to summarise the technologies and applications of gene modification in mice. The first section discusses mouse embryology and the introduction of new gene combinations by microinjection of DNA into pronuclei. The next section reviews the generation of embryonic stem cells (ES cells) and their exploitation, in tissue culture, for the introduction of targeted modifications into endogenous gene loci. The final section discusses more recent technological developments, including the use of IRES elements, CRE-lox recombination, two-step modification to produce subtle mutations, and introduces inducible and tissue-specific gene inactivation (see the presentation by Dr. Isabelle Mansuy). The lecture will conclude with a discussion of the gene-trap strategy and the systematic generation of gene knockouts (Skarnes, 1993; SkarSteel et al., 1998; nes et al., 1995; Townley et al., 1997; Lexicon Inc, 1999).