Gamete (sperm and oocyte) genomes are transcriptionally silent until embryonic genome activation (EGA) following fertilization. EGA in humans had been thought to occur around the eight-cell stage, but recent findings suggest that it is triggered in one-cell embryos, by fertilization. Phosphorylation and other post-translational modifications during fertilization may instate transcriptionally favorable chromatin and activate oocyte-derived transcription factors (TFs) to initiate EGA. Expressed genes lay on cancer-associated pathways and their identities predict upregulation by MYC and other cancer-associated TFs. One interpretation of this is that the onset of EGA, and the somatic cell trajectory to cancer, are mechanistically related: cancer initiates epigenetically. We describe how fertilization might be linked to the initiation of EGA and involve distinctive processes recapitulated in cancer.