A comprehensive analysis of transcriptome dynamics from oocyte to morula in both human and mouse embryos was conducted using single-cell RNA sequencing. The study identified novel stage-specific monoallelic expression patterns for a significant portion of polymorphic gene transcripts (25 to 53%). Weighted gene co-expression network analysis revealed that each developmental stage can be delineated by a small number of functional modules of co-expressed genes, indicating a sequential order of transcriptional changes in pathways of cell cycle, gene regulation, translation and metabolism. Cross-species comparisons showed that the majority of human stage-specific modules are preserved in mouse, but developmental specificity and timing differ between the two species. The study also identified conserved key members of the human and mouse networks, which are likely to be key in driving mammalian pre-implantation development. The results provide a valuable resource to dissect gene regulatory mechanisms underlying progressive development of early mammalian embryos. The study used single-cell RNA sequencing to enable base-resolution scrutiny without confounding effects from cell population heterogeneity. The study traced parent-of-origin allelic RNA transcripts through SNV analysis in pre-implantation embryos. The study identified paternally or maternally expressed genes and found that 53% of 8-cell embryo transcripts and 23% of morula transcripts exhibit monoallelic maternal expression patterns. The study also identified conserved key members of the human and mouse networks, which are likely to be key in driving mammalian pre-implantation development. The study used WGCNA to identify stage-specific co-expression modules, which represent core gene networks operating in each transitional stage. The study found that human and mouse share many core transcriptional programs in early development, but diverge in their stage-specificity and timing. The study identified intramodular hub genes, which are centrally located in their respective modules and may be critical components within the network. The study demonstrated that single-cell RNA sequencing has markedly improved transcriptome quantification of rare human pre-implantation embryo samples at both individual transcript and system levels. The study highlights an evolutionarily conserved molecular process including key genes that drive mammalian pre-implantation development. The study also shows that single-cell RNA-seq can quantitatively delineate the structures, isoforms, and allele-specific expression patterns of both coding genes and non-coding regulatory RNAs. The study concludes that single-cell RNA-seq of a single blastomere could be a promising approach for pre-implantation genetic diagnosis in the near future.A comprehensive analysis of transcriptome dynamics from oocyte to morula in both human and mouse embryos was conducted using single-cell RNA sequencing. The study identified novel stage-specific monoallelic expression patterns for a significant portion of polymorphic gene transcripts (25 to 53%). Weighted gene co-expression network analysis revealed that each developmental stage can be delineated by a small number of functional modules of co-expressed genes, indicating a sequential order of transcriptional changes in pathways of cell cycle, gene regulation, translation and metabolism. Cross-species comparisons showed that the majority of human stage-specific modules are preserved in mouse, but developmental specificity and timing differ between the two species. The study also identified conserved key members of the human and mouse networks, which are likely to be key in driving mammalian pre-implantation development. The results provide a valuable resource to dissect gene regulatory mechanisms underlying progressive development of early mammalian embryos. The study used single-cell RNA sequencing to enable base-resolution scrutiny without confounding effects from cell population heterogeneity. The study traced parent-of-origin allelic RNA transcripts through SNV analysis in pre-implantation embryos. The study identified paternally or maternally expressed genes and found that 53% of 8-cell embryo transcripts and 23% of morula transcripts exhibit monoallelic maternal expression patterns. The study also identified conserved key members of the human and mouse networks, which are likely to be key in driving mammalian pre-implantation development. The study used WGCNA to identify stage-specific co-expression modules, which represent core gene networks operating in each transitional stage. The study found that human and mouse share many core transcriptional programs in early development, but diverge in their stage-specificity and timing. The study identified intramodular hub genes, which are centrally located in their respective modules and may be critical components within the network. The study demonstrated that single-cell RNA sequencing has markedly improved transcriptome quantification of rare human pre-implantation embryo samples at both individual transcript and system levels. The study highlights an evolutionarily conserved molecular process including key genes that drive mammalian pre-implantation development. The study also shows that single-cell RNA-seq can quantitatively delineate the structures, isoforms, and allele-specific expression patterns of both coding genes and non-coding regulatory RNAs. The study concludes that single-cell RNA-seq of a single blastomere could be a promising approach for pre-implantation genetic diagnosis in the near future.