For decades, scientists studying mammalian cells could only marvel at the genetic tools available to scientists who studied organisms such as yeasts or drosophila. However, many genes linked to human diseases do not have orthologs in such model organisms, or they require an appropriate cellular context to display their disease-relevant phenotypes. The wish for a facile method to disrupt gene function in somatic mammalian cells appeared to be granted with the discovery of RNA interference (RNAi) and small interfering RNA (siRNA) (or short hairpin RNA, shRNA), which brought with them great promise—particularly for discovering novel drug targets through the use of genetic screens (–). However, the honeymoon is now over, and although some new discoveries have been made, the yield has fallen far short of expectations. Many drug targets identified by means of si/shRNA technology in academic laboratories are not robust when tested in industrial laboratories (, ). Avoiding this fate requires a more sophisticated interpretation of si/shRNA results, especially in the context of high-throughput screens.