RNA interference (RNAi) is an evolutionary conserved gene-silencing mechanism in which 21- to 23-mer double-stranded short interfering RNA (siRNA) mediates the sequence-specific degradation of mRNA. The recent discovery that exogenously delivered siRNA can trigger RNAi in mammalian cells raises the possibility of using this technology as a therapeutic tool against pathogenic viruses. This review describes the antiviral RNAi field, which is barely two years-old, with an emphasis on recent studies aimed at suppression of HIV-1.