The vertebrate genome is under constant threat of invasion by genetic parasites. Whether the host can immediately recognize and respond to invading elements has been unclear. The discovery of the human silencing hub (HUSH) complex, and the finding that it provides immediate protection from genome invasion by silencing products of reverse transcription, have important implications for mammalian genome evolution. In this review, we summarize recent insights into HUSH function and describe how cellular introns provide a novel means of self–nonself discrimination, allowing HUSH to recognize and transcriptionally repress a broad range of intronless genetic elements. We discuss how HUSH contributes to genome evolution, and highlight studies reporting the critical role of HUSH in development and implicating HUSH in the control of immune signaling and cancer progression.