Reprogramming cells carrying a third chromosome resulted in the loss of the extra chromosome in mice and human cells, scientists report, which could eventually pave the way to novel approaches that treat developmental defects or infertilities associated with extra chromosomes. An incorrect number of chromosomes is known to cause altered development, infertility, or death, and among such related disorders, sex chromosome trisomy (SCT) afflicts 0.1% of the human population. Here, Takayuki Hirota and colleagues showed that when fibroblasts from sterile trisomic XXY and XYY rodents were reprogrammed to induced pluripotent stem cells (iPSCs), the animals frequently lost the extra sex chromosome, an observation they referred to as trisomy-biased chromosome loss (TCL). The corrected XY iPSCs successfully developed into germ cell lineages upon transplantation into mouse testes, giving rise to sperm that were able to produce chromosomally normal and fertile offspring. The researchers showed similar chromosome loss with non-sex chromosome trisomies in a mouse model of Down syndrome, as well as chromosome loss in trisomic human cells. The authors say that TCL also allows the generation of female iPSCs from males, offering the potential for further investigation on a genetic level of sexual dimorphisms. Hirota et al. further note that with additional investigation, sex differences identified during iPSC disease modeling may be attributed to X or Y specific chromosomal effects.