Placental mammals compensate the dosage imbalance of X-linked genes between males (XY) and females (XX) by silencing one randomly chosen X chromosome in females. This process is initiated during early embryonic development and can be recapitulated during differentiation of murine embryonic stem cells (mESCs). X chromosome inactivation (XCI) is initiated by up-regulation of a non-coding RNA on the future inactive X chromosome, named Xist, which lies within a large complex locus, called the X inactivation center (Xic). Subsequently, Xist RNA induces silencing of the entire chromosome in cis. Although central to the XCI process, the molecular mechanisms underlying Xist's regulation still remain to be deciphered. In particular, it is unclear (1) how the up-regulation of Xist is triggered at the onset of differentiation, (2) why this is restricted to female cells, and (3) why one allele and not the other is affected? Although each aspect could in principle be controlled by distinct factors and sequence elements, one protein has recently been proposed to regulate Xist at all three levels: the E3 ubiquitin ligase Rnf12/Rlim. The X-linked Rnf12 gene acts as a dose-dependent activator of Xist, which is expressed at elevated levels in female relative to male cells and is up-regulated during differentiation. Two recent studies shed further light on the precise role of Rnf12 in XCI.