Sequences of retroviral origins are abundant in the human genome, but their functional significance remains poorly understood. Frank et al. identified a pool of sequences derived from retroviral envelopes (which normally facilitate viral entry into cells) that are expressed during human fetal development, viral infection, and immune stimulation (see the Perspective by Padilla Del Valle and McLaughlin). The authors hypothesized that some of these sequences encode proteins with antiviral activity by binding to and competing for cell surface receptors targeted by infectious viruses. Genetic manipulation in cell culture showed that one such protein, SUPYN, was capable of restricting infection by type D retroviruses circulating in several mammals. —DJ