Presently, Phase III efficacy trials with subunit immune antigens against the human immunodeficiency virus (HIV) infection are occurring in both the USA and some Southeast Asian countries. However, there is no feeling of dèja vu within the scientific community that these studies will demonstrate meaningful protection against HIV infection, perhaps because the immune responses crucial for containment of the virus might not be elicited by this approach. Under this prevailing gloomy setting for international acquired immune deficiency syndrome (AIDS) therapy, RNA interference has been identified as a likely strategy in the understanding that inhibition of HIV replication can be mediated by post-transcriptional gene silencing through the production of double-stranded RNA (dsRNA) nucleotide intermediates. This review briefly explores the role of the nef gene during HIV-1 infection and highlights the expectation that RNA interference might serve as a new sequence-specific therapeutic arsenal in AIDS prevention, and possibly treatment, in the years ahead.