RNA interference seemed poised to transform functional genomics and therapeutics with the 2001 publication of a paper by Tom Tuschl and colleagues showing that 21-base-pair (bp) RNA duplexes silence mammalian genes in a sequence-dependent manner.[1] Though prior research demonstrated the effectiveness of double-stranded (ds)RNA as a posttranscriptional gene-silencing tool in plants and nematodes, its use in mammals was limited by the fact that dsRNAs larger than 30 bp can activate the interferon response through a PKR kinase-mediated pathway. After Tuschl's research was published, RNAi scientists were optimistic that so-called short interfering (si)RNAs were the answer to this problem.