This chapter discusses human immunodeficiency virus type 1 (HIV-1) associated with CD4 downmodulation. It also discusses the structure and function of CD4 and p56lck and factors involved in hiv-1-associated cd4 downmodulation. There are, at present, at least three HIV-1 gene products known to be involved in cell surface CD4 downmodulation. These are Nef, Vpu, and gp160. Whereas Nef is expressed during the early phase of HIV-1 gene expression, both Vpu and gp160, which appear to act coordinately, are expressed during the late phase. This functional convergence of HIV-1 proteins on cell surface CD4 downmodulation, whether specific or nonspecific in activity, suggests that this event is of critical importance in the life cycle of HIV-1. Further elucidation of the mechanisms that underlie CD4 cell surface downmodulation may lead to the development of novel strategies aimed at preventing such events, and potentially to the development of new therapeutic approaches.