In females, most genes on the inactive X Chromosome (Chr) are transcriptionally silenced. However, several dozen genes have been identified in human that escape inactivation and are expressed from both the active and inactive X Chrs. Many of the genes that escape inactivation in human are subject to inactivation in mouse, raising questions concerning the mechanisms that govern expression from the inactive X Chr in the two species. In human, the existence of a cluster of genes in Xp11.21-p11.22 that escape inactivation suggests that control of X inactivation occurs at the level of chromosomal domains. In this study, we have isolated, physically mapped, and determined the X inactivation status of a number of the orthologous mouse genes that correspond to this human "escape domain". In contrast to human, only the mouse Smcx gene has been found to escape inactivation in this region thus far, despite a highly conserved physical map between the two species. Sequence analysis and functional characterization of the mouse Smcx promoter did not reveal any obvious unique features that would explain the difference in the behavior of this gene on the inactive X compared with other nearby genes. Possible mechanisms responsible for the differing inactivation status between genes in the escape domain in human Xp11. 21-p11.22 and the corresponding mouse region are discussed.