The ZFY gene in the sex-determining region of the human Y chromosome encodes a protein with 13 zinc fingers, and may determine whether an embryo develops as a male or female. ZFX, a related gene on the human X chromosome, may also function in sex determination; it encodes a protein with a very similar zinc-finger domain and escapes X inactivation. ZFY and ZFX diverged from a common ancestral gene before the radiation of placental mammals, and retain a similar genomic organization. Analysis of complementary DNAs from the mouse Y-chromosomal homologues of ZFY indicates that these genes encode probable transcription activators. Here, we report that ZFX encodes a protein composed of a highly acidic amino-terminal domain, a basic putative nuclear-localization signal, and a carboxy-terminal zinc-finger domain. This combination of features, also found in the ZFY gene product, is typical of transcription activators. Alternative splicing generates ZFX transcripts encoding isoforms of 575 and 804 amino acids. These ZFX protein isoforms differ in the length of their acidic domains and may be functionally distinct.