The FBXL10 protein (also known as KDM2B, JHDM1B, CXXC2, and NDY1) is bound to essentially all CpG-rich promoters in the mammalian genome. FBXL10 is expressed as two isoforms: FBXL10-1, a longer form that contains an N-terminal JmjC domain with C- terminal F-box, CXXC, PHD, RING, and leucine rich repeat (LRR) domains, and FBXL10-2, a shorter form that initiates at an alternative internal exon and which lacks the JmjC domain but retains the other domains. Selective deletion of Fbxl10-1 had been reported to produce a minor and variable phenotype, and most mutant animals were essentially normal. We show here that deletion of Fbxl10-2 (in a manner that does not perturb expression of Fbxl10-1) resulted in a very different phenotype with craniofacial abnormalities, greatly increased lethality, and female sterility in surviving homozygous mutants. The phenotype of the Fbxl10-2 deletion was more severe in female mutants. We found that mutants that lacked both FBXL10-1 and -2 showed embryonic lethality and even more extreme sexual dimorphism, with more severe gene dysregulation in mutant female embryos. X-linked genes were most severely dysregulated, and there was marked overexpression of Xist in mutant females although genes that encode factors that bind to Xist RNA were globally down-regulated in mutant female as compared to male embryos. FBXL10 is the first factor shown to be required both for the normal expression and function of the Xist gene. Expression analysis using RNA-seq was performed on WT and Fbxl10T/T male and female embryos.