While investigating the genetic workings of the microscopic worm, C. elegans, Mello and colleague Andrew Fire, PhD, of the Carnegie Institution of Washington, discovered RNAi, a natural but previously unrecognized process by which a certain form of RNA can be manipulated to silence—or interfere with—the expression of a selected gene. The discovery, published in the journal Nature in 1998, has had two extraordinary impacts on biological science. One is as a research tool: RNAi is now the state-of-the-art method by which scientists can knock out the expression of specific genes in cells, to thus define the biological functions of those genes. But just as important has been the finding that RNA interference is a normal process of genetic regulation that takes place during development. Thus, RNAi has provided not only a powerful research tool for experimentally knocking out the expression of specific genes, but has opened a completely new and totally unanticipated window on developmental gene regulation. RNAi is now showing promising in the clinic as a new class of gene-specific therapeutics.