The human genome bears traces of past retroviral infections in the form of endogenous retroviruses (ERVs) whose long terminal repeats (LTRs) contain cis-regulatory elements that affect gene activity. The evolutionarily most recent member of the human ERV family, HERVK, retains intact open reading frames (ORFs) encoding retroviral proteins that are normally silenced by DNA methylation. Now Wysocka and colleagues show that HERVK transcription is activated during human embryogenesis, with likely effects on early development. Analysis of single-cell RNA-sequencing profiles at different embryonic stages revealed active HERVK transcription at the eight-cell stage and in epiblast cells (ECs) of the preimplantation blastocyst; this transcription is then silenced upon blastocyst outgrowth. Similarly, HERVK transcripts are present in naive human embryonic stem cells (ESCs) that correspond to the preimplantation state but not in primed ESCs, thus suggesting that HERVK expression is induced during a transient window when DNA is hypomethylated and regulatory elements are accessible to the pluripotency factors OCT4 and SOX2. Indeed, the authors show that the LTR of HERVK contains an OCT4-binding motif that is engaged by the transcription factor in ECs but not primed ESCs. DNA hypomethylation is required for OCT4-dependent activation, which promotes stage-specific expression of proviral proteins. Most remarkably, transmission electron microscopy shows that human blastocysts contain numerous viral-like particles. Moreover, expression of HERVK Rec, a protein that exports viral RNAs to the cytosol for translation, induces innate-antiviral-response components in ECs and increases the levels of the interferon-induced viral restriction factor IFITM1. Importantly, Rec overexpression is sufficient to confer resistance to influenza virus infection in EC cell lines, thus suggesting that HERVK might provide an immunoprotective effect during preimplantation development. Wysocka and colleagues also identified ∼1,600 cellular RNAs that are bound by Rec, and ribosome profiling suggested that their translation is stimulated by Rec association. The finding that HERVK proteins are expressed in early embryogenesis and are able to influence host factors reveals an unexpected role for products of ancient retroviral infection during human embryonic development. (Nature 10.1038/nature14308, 20 April 2015)