Zfp42/Rex1 (reduced expression gene 1) is a well-known stem-cell marker that has been duplicated from YY1 in the eutherian lineage. In the current study, we characterized the in vivo roles of Rex1 using a mutant mouse line disrupting its transcription. In contrast to the ubiquitous expression of YY1, Rex1 is expressed only during spermatogenesis and early embryogenesis and also in a very limited area of the placenta. Yet, the gene dosage of Rex1 is very critical for the survival of the late-stage embryos and neonates. This delayed phenotypic consequence suggests potential roles for Rex1 in establishing and maintaining unknown epigenetic modifications. Consistently, Rex1-null blastocysts display hypermethylation in the differentially methylated regions (DMRs) of Peg3 and Gnas imprinted domains, which are known to contain YY1 binding sites. Further analyses confirmed in vivo binding of Rex1 only to the unmethylated allele of these two regions. Thus, Rex1 may function as a protector for these DMRs against DNA methylation. Overall, the functional connection of Rex1 to genomic imprinting represents another case where newly made genes have co-evolved with lineage-specific phenomena.