Inactivation of one of the two X chromosomes in females is regulated by sequences on the X-chromosome within the X inactivation center (Xic). In the May 10 Science, Percec et al. report the identification of trans-acting autosomal elements involved in choosing the particular X chromosome for inactivation (Science 2002, 296:1136-1139). They performed a phenotype-driven genetic screen for mutations that affect X-chromosome silencing choices in mice: they screened mice from parents exposed to chemical mutagens and looked for changes in X-chrmosome inactivation patterns. They then identified two mutant females that transmitted altered X inactivation patterns to early embryos. Both mutations exhibited autosomal dominant modes of inheritance. Percec et al. mapped one of these mutations to mouse chromosome 15; characterization of these autosomal factors (named Xiaf1 and Xiaf2) should provide insights into the molecular mechanisms underlying the complex epigenetic process of x-chromosome inactivation.