The interferon-inducible, transmembrane protein BST-2 (CD317, tetherin) directly holds fully formed enveloped virus particles to the cells that produce them, inhibiting their spread. BST-2 inhibits members of the retrovirus, filovirus, arenavirus and herpesvirus families. These viruses encode a variety of proteins to degrade BST-2 and/or direct it away from its site of action at the cell surface. Viral antagonism has subjected BST-2 to positive selection, leading to species-specific differences that presented a barrier to the transmission of simian immunodeficiency viruses (SIVs) to humans. This barrier was crossed by HIV-1 when its Vpu protein acquired activity as a BST-2 antagonist. Here, we review this new host-pathogen relationship and discuss its impact on the evolution of primate lentiviruses and the origins of the HIV pandemic.