The ZFX gene on the human X chromosome is structurally similar to the ZFY gene, which may constitute the sex-determining signal on the human Y chromosome. ZFY and ZFX diverged from a common ancestral gene, as evidenced by similarities in their intron/exon organization and exon DNA sequences. The carboxy-terminal exons of ZFY and ZFX both encode 13 zinc fingers; 383 of 393 amino acid residues are identical, and there are no insertions or deletions. Thus, the ZFY and ZFX proteins may bind to the same nucleic acid sequences. ZFY and ZFX are transcribed in a wide variety of XY and (in the case of ZFX) XX cell lines. Transcription analysis of human-rodent hybrid cell lines containing "inactive" human X chromosomes suggests that ZFX escapes X inactivation. This result contradicts the "dosage/X-inactivation" model, which postulated that sex is determined by the total amount of functionally interchangeable ZFY and ZFX proteins.