Pathogenic retroviruses have driven the evolution of several dominant-acting mechanisms able to block infection and protect the host. These are exemplified by the mouse gene Fv1, which encodes a Gag-like protein able to protect against murine leukemia virus (MLV) infection. The block is saturable, occurs after reverse transcription and is directed against the viral capsid gene. Several other mammalian species are also able to block MLV infection with the same capsid specificity. A human gene with this activity has been named Ref1. Recently, primates have been shown to restrict a variety of retroviruses only very distantly related to MLVs through a gene named Lv1. Restricted viruses include MLV as well as lentiviruses such as human immunodeficiency viruses 1 and 2, simian immunodeficiency virus and equine infectious anemia virus. In each case the block to one retrovirus can be saturated by co-infection with a second restricted virus. The possible mechanisms of action, and evolutionary consequences of restriction, are reviewed.