The Vpu protein of human immunodeficiency virus type 1 (HIV-1) is a transmembrane protein that is synthesized late in the virus life cycle but is not incorporated into mature virions. Vpu has been shown to have two major functions in the life cycle of HIV-1. Vpu has been shown to interact with the CD4 molecule (in the rough endoplasmic reticulum; RER), which is the receptor for HIV-1 entry. This interaction is thought to result in re-translocation of the CD4 molecule across the RER and subsequent degradation via the proteasome pathway. In addition, Vpu has been shown to enhance virion release from infected cells by a yet undetermined mechanism. While much has been learned about the function of Vpu in cell culture systems, its exact role in HIV-1 pathogenesis (HIV-1 only causes disease in humans and chimpanzees) is still unknown. This is due to the lack of a suitable primate model system since vpu is found only in HIV-1 and simian immunodeficiency virus (SIV) isolated from chimpanzees (SIVcpz). The most commonly used virus to model HIV-1 pathogenesis, SIV from macaques, does not encode for a Vpu protein. With the recent development of the pathogenic simian-human immunodeficiency virus (SHIV)/macaque model, in which the tat, rev, vpu and env genes of HIV-1 are expressed in the genetic background of SIV, it will now be possible to assess the role of the vpu gene product in a relevant animal model. This article will review the current understanding of the structure-function relationships of Vpu protein and the use of the SHIV/ pig-tailed macaque system as a animal model to assess the role of Vpu in HIV-1 pathogenesis.