At least 8% of all human conceptions have major chromosome abnormalities and the frequency of chromosomal syndromes in newborns is >0.5%. Despite these disorders making a large contribution to human morbidity and mortality, we have little understanding of their aetiology and little molecular data on the importance of gene dosage to mammalian cells. Trisomy 21, which results in Down syndrome (DS), is the most frequent aneuploidy in humans (1 in 600 live births, up to 1 in 150 pregnancies world-wide) and is the most common known genetic cause of mental retardation. To investigate the molecular genetics of DS, we report here the creation of mice that carry different human chromosome 21 (Hsa21) fragments as a freely segregating extra chromosome. To produce these 'transchromosomal' animals, we placed a selectable marker into Hsa21 and transferred the chromosome from a human somatic cell line into mouse embryonic stem (ES) cells using irradiation microcell-mediated chromosome transfer (XMMCT). 'Transchromosomal' ES cells containing different Hsa21 regions ranging in size from approximately 50 to approximately 0.2 Mb have been used to create chimeric mice. These mice maintain Hsa21 sequences and express Hsa21 genes in multiple tissues. This novel use of the XMMCT protocol is applicable to investigations requiring the transfer of large chromosomal regions into ES or other cells and, in particular, the modelling of DS and other human aneuploidy syndromes.