HIV type 1 (HIV-1) has a very narrow host range that is limited to humans and chimpanzees. HIV-1 cannot replicate well in Old World monkey cells such as rhesus and cynomolgus monkeys. Tripartite motif (TRIM)5α is a key molecule that confers potent resistance against HIV-1 infection and is composed of really interesting new gene, B-box2, coiled-coil and PRYSPRY domains. Interaction between TRIM5α PRYSPRY domains and HIV-1 capsid core triggers the anti-HIV-1 activity of TRIM5α. Analysis of natural HIV variants and extensive mutational experiments has revealed the presence of critical amino acid residues in both the PRYSPRY domain and HIV capsid for potent HIV suppression by TRIM5α. Genetic manipulation of the human TRIM5 gene could establish human cells totally resistant to HIV-1, which may lead to a cure for HIV-1 infection in the future.