1. Abstract/Primer Abstract/Primer: Over the past several decades, it has become clear that a variety of cellular proteins actively restrict retrovirus replication. Two families of proteins in particular, the TRIMs and the APOBEC3s, coordinate a robust innate defense to retrovirus infection. The TRIM proteins, led by TRIM5alpha, impose a replication block after entry, such that the invading retrovirus is degraded prior to integration. The APOBEC3 proteins, notably APOBEC3G, inhibit the replication of retroviruses by a mutagenic mechanism that is associated with degradation of viral DNA. Retroviruses have evolved means of avoiding their host's TRIM and APOBEC3 defenses. Often, however, this leaves the virus susceptible to TRIMs and APOBECs from other species. Thus, these restriction systems limit the cross-species mobility of retroviruses. The prospects of developing new antiviral therapies that exploit these innate host defenses are promising.