In a genome-wide analysis, we have identified 85 human genes encoding 103 protein isoforms that resemble retroviral Gag proteins. These genes were domesticated from retrotransposons in at least five independent events during vertebrate evolution and were subsequently duplicated further in mammals. Structural insights into the mammalian proteins can be inferred by homology to Gag from viruses such as HIV; in turn, the cellular roles of the mammalian Gag homologs, such as apoptosis-related functions and binding to ubiquitin ligases, might hint at further functionality of viral Gag itself.