The transcriptional awakening of the zygotic genome in early embryos is fundamental for the start of life. upon fertilization of an egg by sperm, zygotic chromatin is assembled into a specialized, closed, and transcriptionally inactive state. the embryo initially relies on maternal stores of rna and protein. soon, however, the synthesis of its own transcripts in a process known as zygotic genome activation (zga) becomes critical for development. of zga by nr5a2 and potentially other orphan nuclear receptors is comparable to zelda in drosophila and the collective activity of three pluripotency factors in zebrafish. developmental, genomic, and biochemical data support a model in which nr5a2 binding at distal cis-regulatory elements promotes chromatin accessibility to initiate zga. we conclude that nr5a2 has properties consistent with pioneer factor activity and activates zga in totipotent embryos. our work provides a conceptual “ex uno plura” (many from one) framework for the robustness of zga by nr5a2-mediated transcriptional activation of related family members. we propose that nr5a2 activates transcription of zga genes, which includes orphan nuclear receptors that can recognize the same motif and potentiate the activation of zga. the classification of nr5a2 as a pioneer factor suggests that the mechanisms triggering zga are evolutionarily conserved from fly to mouse and possibly to human, despite species-specific differences in hitherto reported transcription factors. however, nr5a2 is conserved in metazoa and maternally provided in embryos of model organisms and humans, which implies an ancestral function in early development. although sine b1 are murine specific, the human genome harbors the related alu retrotransposable elements that also contain nr5a2 motifs. we speculate that the regulation of zga by orphan nuclear receptors such as nr5a2 is a conserved mechanism, at least among mammals. zga is triggered by maternally pro