Double‐stranded RNA interference (ds RNA i) represents a primary means of anti‐viral defense in plants, worms, and insects, yet appears mostly supplanted by the protein‐based interferon ( IFN ) response in vertebrates such as mammals. The degree to which ds RNA i is anti‐viral in mammals has been contentious. Maillard et al ( ) find that ds RNA i retains sequence‐specific silencing in mammalian cells incapable of triggering an IFN response, suggesting that ds RNA i is inhibited by the action of interferon‐stimulated genes. Importantly, they observe that while ds RNA can “vaccinate” against the incoming cognate virus though ds RNA i silencing, no ds RNA i is observed with viral infection alone, suggesting that this evolutionarily conserved anti‐viral pathway is present but functionally elusive in the cell types studied thus far.