In the last few years the major effect that RNAi has had in invertebrate systems is beginning to take hold in mammalian systems through both single gene knockdown experiments and genome-scale screens. In the next decade, there will no doubt be both notable successes and failures as we attempt to apply this genetic tool to various biological problems. Through the introduction of RNAi, mammalian systems have finally gained admittance to the pantheon of model genetic systems.