Human endogenous retroviruses (HERVs) are kept silent to a large extent to minimize retrotransposition and genomic instability. Lu et al. studied the HERV-H subfamily, which are selectively re-expressed in embryonic stem cells. They found that HERV-H knockdown induced differentiation, indicating that HERV-H expression has an active and useful role in maintaining pluripotency. Mechanistic investigations revealed that HERV-H transcripts bind to OCT4 and co-activators to contribute to a pluripotency-associated transcriptional network.