Researchers have successfully replaced the Y chromosome in mice while preserving the male's ability to produce offspring. They achieved this technical feat by increasing expression of just two genes. These developments provide new insights into the role of the Y chromosome in reproduction and determining sex. The sex chromosomes differ between males and females; women have two X chromosomes, while men have one X and one Y chromosome. Thus, the Y chromosome is known as a biologically defining feature of men. In this Report, Yasuhiro Yamauchi and colleagues build upon previous work, where they found that only two genes - Sry and Eif2s3y - are needed from the Y chromosome for male mice to successfully reproduce. This led them to explore whether overexpression of genes on other chromosomes could replace the functioning of these Y chromosome genes. Although mice lacking Y chromosome DNA had abnormal testes and sperm that could not proliferate, inducing expression of Sox9, a SRY target gene, and an Eif2s3y homolog on the X chromosome allowed the sperm to proliferate. The team then tested these sperm using artificial fertilization techniques, finding that nine out of 13 male mice lacking Y chromosome DNA were able to produce offspring. The authors find that the X chromosome counterpart for Eif2s3y compensates for Eif2s3y at a ratio that is not one-to-one (indeed, the X chromosome counterpart is expressed at a lower level). The exchangeability of Y chromosome genes with those encoded on other chromosomes demonstrates the plasticity of the mammalian genome.