To gain insight into how epigenetic aberrations arise during genomic reprogramming in mammalian preimplantation embryos, Daniel Messerschmidt, William Burkholder and colleagues developed an assay to measure DNA methylation in single cells (Science 341, 1110–1112, 2013). They analyzed DNA methylation at six imprinted loci after genetically manipulating Trim28, which encodes a DNMT1-binding protein and is known to be required for the maintenance of differential methylation at imprinted loci in preimplantation embryos. They examined blastomeres from eight-cell embryos after maternal Trim28 knockout and observed variable aberrant methylation patterns indicative of embryos that consisted of mixtures of normally and aberrantly imprinted cells. The authors further defined the temporal requirement for TRIM28 by transferring control or maternal Trim28-null pronuclei into enucleated control or Trim28-null zygotes. They found that removal of maternal TRIM28 reduced zygote survival, and supply of maternal TRIM28 increased zygote survival, showing that maternal TRIM28 is required after fertilization. These authors previously showed that loss of maternal TRIM28 causes phenotypic variability and embryonic lethality. This new work demonstrates that loss of maternal TRIM28 creates epigenetic chimeras and may explain the phenotypic variability of the embryos that result from loss of maternal TRIM28.