Antibody-dependent enhancement (ADE) of infection has been described for a number of viruses including HIV-1. However, the biological role of ADE in HIV disease pathogenesis or in increasing the risk of infection upon exposure is uncertain. In this review, we outline the mechanisms of ADE, as ascertained in vitro. We also discuss several recent human and non-human primate studies that raise concern about ADE resulting from vaccine-induced or passively infused antibodies. Although biologically plausible, an important role for ADE in natural HIV infection has not been directly confirmed. Nonetheless, there is a need for further studies to pinpoint the exact mechanism or mechanisms at play in vivo and, more importantly, to develop assays that can predict the likelihood that a vaccine or antibody infusion will lead to enhanced infection or pathogenesis.