Adaptation of the P1 phage-derived Cre/loxP site-specific recombination system to the gene targeting technique allows for the conditional deletion of genes in mice. To selectively modify genes in B lymphocytes, we have generated mice (designated CD19-Cre) which express cre under the transcriptional control of the B lineage-restricted CD19 gene. In a model system involving the cross of CD19-Cre mice with mice bearing a /oxP-flanked substrate, we find a deletion efficiency of 75–80% in bone marrow-derived pre-B cells that increases to 90–95% in splenic B cells.