The SIV family is a diverse group of viruses that vary considerably in pathogenesis and virulence in their natural host species or macaques. Although the disease induced by the SIVsm subtype in particular is remarkably similar to human AIDS, it must be remembered that this is an experimental animal model. Therefore, although the pathogenesis of SIVsm (and other viruses) in macaques offers an relevant animal model for pathogenesis and vaccine trials, the interactions of these viruses in their natural host, and virus-, or host-specific effects have been poorly characterized. This animal model offers a unique opportunity to study the details of the pathogenesis of immunodeficiency and to define host and viral factors responsible for disease progression.