RNAi versus small molecules: different mechanisms and specificities can lead to different outcomes

The methodology of RNA interference (RNAi) arrived on the scene of mammalian systems research in 2001. Since that time, there has been widespread use of this technology in both academic and industrial settings. RNAi and small molecules were initially considered as equivalent methods for inhibiting protein activity within cells, but as our understanding of the mechanism of RNAi has improved, it has become apparent that differences in their cellular mechanisms have unexpected consequences. There can be profound differences in the phenotypic outcomes of treatment with RNAi versus small molecules. This review discusses the similarities, as well as the predicted differences between RNAi and small molecule effects on therapeutic paradigms and drug discovery.