Detailed deletion analysis of patients with breakpoints in Yp has allowed the definition of two distinct intervals on the Y chromosome short arm outside the pseudoautosomal region that are homologous to Xq21.3. Detailed YAC contigs have been developed over these regions on both the X and Y chromosomes, and the relative order of markers has been compared to assess whether rearrangements on either sex chromosome have occurred since the transposition events creating these patterns of homology. On the X chromosome, the region forms almost one contiguous block of homology, whereas on the Y chromosome, there has been one major rearrangement leading to the two separate Yp–Xq21 blocks of homology. The rearrangement breakpoint has been mapped. Within these separate X–Y homologous blocks on Yp, the order of loci homologous to X has been conserved to a high degree between the sex chromosomes. With the exception of the amelogenin gene (proximal Yp block), all the X–Y homologous sequences in the two Yp blocks have homologues in Xq21.3, with the former having its X counterpart in Xp22.2. This suggests an independent evolutionary event leading to the formation of the amelogenin X–Y homology.