It is possible to create mice in which a planned alteration has been introduced at a specific locus in the genome. The planned alteration is first introduced into the genome of mouse embryonic stem (ES) cells in tissue culture. This is accomplished by homologous recombination between the targeted genomic locus and DNA introduced into the ES cells. Cells containing the desired alteration are injected into recipient blastocysts for return to pseudo-pregnant foster mothers, where they can develop into chimeric pups. ES cells that contribute to the germline of the resulting chimeric mice allow the altered ES cell genome to be transmitted to future generations. This technique provides a powerful tool for exploring the mechanisms underlying the development and function of the immune system in vivo.