Functional studies of large transcription units, clustered genes and chromosomal loci require the design of novel experimental tools to engineer genomic macro-rearrangements. Here, we present a strategy to produce deficiencies or duplications by crossing mice carrying loxP sites in homologous loci. This trans-allelic targeted meiotic recombination (TAMERE) protocol allows for the combination of various alleles within a particular locus as well as for generation of interchromosomal unequal exchanges. Novel genetic configurations can thus be produced without multiple targeting and selection steps in embryonic stem (ES) cells. A concomitant deletion/duplication event of the Hoxdl2 locus shows the potential of this approach. The high frequency of such targeted exchanges in vivo makes TAMERE a powerful genetic tool applicable to research areas in which complex genomic modifications are required.