Protocadherins are members of the cadherin superfamily involved in cell-cell interactions critical in the development of the central nervous system. This paper describes the isolation, sequence, and expression analysis of two novel protocadherin genes from the hominid specific Yp11.2/Xq21.3 block of homology between the sex chromosomes. The X-(PCDHX) and Y-linked (PCDHY) genes share 98.1% nucleotide and 98.3% amino acid identity and have an identical gene structure of six exons. The open reading frames of PCDHX and PCDHY encode proteins of 1025 and 1037 amino acids respectively and specify seven extracellular cadherin domains. Small differences in amino acid sequence affect regions that potentially have a large impact on function: thus, the X and Y genes may be differentiated in this respect. Sequence analysis of cDNA clones shows that both the X and Y loci are transcribed. RT-PCR expression analysis of mRNA from a variety of tissues and cell lines has demonstrated that both transcripts are expressed predominantly in the brain, with differential regional expression. From studies in the NTERA pluripotential cell line (which differentiates along neuronal and spermatogenic pathways in response to retinoic acid), it emerges that the X and Y-linked genes are regulated differently. This indicates that PCDHX and PCDHY possess different promoter regions. These findings suggest a role for PCDHX and PCDHY in the brain, consistent with the involvement of protocadherins in segmental brain morphogenesis and function. The implications of Y-linked genes expressed predominantly in tissues and organs other than the testis are considered within the context of the concept of sexual selection.