The murine Xlr (X-chromosome linked lymphocyte-regulated) gene family was originally identified by subtractive cDNA cloning and hybridization. A single predominant functional transcript encoding a 25 kDa peptide was initially found to be expressed in lymphoid cell lines corresponding to late stages of differentiation. A second functional Xlr gene has now been defined. It is expressed in differentiating male germ cells. Both the lymphoid and the germinal cell Xlr proteins are located in the cell nucleus and are closely homologous to each other. In parallel with the small number of currently known functional transcripts, the Xlr family comprises 50-75 sequences per haploid genome of which a majority is nonfunctional and that are localized on the proximal half of the X-chromosome and also on the Y-chromosome. This accumulation of pseudogenes may be related to the evolutionarily recent amplification of Xlr in rodents. Although murine Xlr probes do not cross-hybridize with human DNA, the existence of a human homolog for Xlr should be nevertheless postulated because of the conservation of X-chromosomal organization in mammals. Possible relationships of Xlr with X-linked primary immune deficiencies in man and mouse are finally discussed.