Double-stranded RNA-mediated interference (RNAi) induces sequence-specific post-transcriptional gene silencing and has emerged as a powerful tool to silence gene expression in multiple organisms. In mammalian cells, duplexes of 21 nucleotide RNAs, known as short-interfering RNAs (siRNAs), efficiently inhibit gene expression. Recent research demonstrates the general use of siRNAs to specifically inhibit HIV-1 replication by targeting viral or cellular genes. Importantly, RNAi opens a new avenue for gene-based therapeutics.