Ascertaining the function of the third hypervariable (V3) region of the HIV-1 surface glycoprotein, gp120, may be essential for understanding several important features of HIV-1 immunopathogenesis and for design-ing effective vaccines against HIV. The V3 loop elicits one of the earliest antiviral antibody responses in both natural and experimental HIV-1 infection, as well as after immunization with native and recombinant gly-coproteins, Within the viral envelope, the V3 domain functions during virus-cell adsorption and fusion, following the initial binding event between gp120 and the CD4 molecule on the surface of target cells. Its sequence variation has a major influence on HTV-1 tropism, in that the sequence and structure of the V3 loop is an important determinant of the efficiency of entry of HIV-1 variants into cells of different lineages. For the commonly studied cell culture-adapted isolates of HIV-1, at least, the V3 region represents the major immunodominant epitope by which both HIV-1 cellfree infectivity and cell-to-cell spread are neutralized by serum antibodies. Yet we understand neither the role of the V3 loop in HIV-1 entry, nor how binding of an antibody to it inhibits this process. In the first part of this review we describe the evidence that implicates the involvement of the V3 loop in the virus-cell fusion reaction; in the second, several hypotheses on the mechanism of this involvement will be discussed, including where and how V3-specific antibody may play a role in inhibiting HIV-1 infection.