The Nef protein of primate lentiviruses acts as an important virulence factor in vivo both in monkeys and in humans. Among a human cohort of long-term non-progressors, several Nef defective HIV1 viruses have been isolated, indicating that Nef may accelerate HIV progression and disease in humans. Additionally, a Nef-deleted SIV virus has low titres in rhesus monkeys and the animals develop AIDS at a much slower rate. In vitro, Nef can exert at least three kinds of effects: it downregulates CD4 and MHC class I, it stimulates virion infectivity and it alters signal transduction pathways. To accomplish this, Nef interacts with a series of cellular partners including CD4, components of the adaptor complexes AP-1 and AP-2, and several protein kinases, Nef often functioning as a connector between targets and effectors. The high degree of understanding of at least some aspects of Nef action, as well as the importance of this viral gene product for disease induction, identify Nef as a valuable target for the development of novel antiviral therapies. Moreover, the possibility of developing vaccines using attenuated viruses with deletions in nef and other crucial genes raises the possibility that the AIDS epidemic might one day be restrained.