RNA interference (RNAi) holds considerable promise as a novel therapeutic strategy to silence disease-causing genes not amenable to conventional therapeutics. Since it relies on small interfering RNAs (siRNAs), which are the mediators of RNAi-induced specific mRNA degradation, a major issue is the delivery of therapeutically active siRNAs into the target tissue. In vivo gene silencing with RNAi has been reported using both viral vector delivery and high-pressure, high-volume intravenous (i.v.) injection of synthetic siRNAs. For safety reasons, strategies based on viral vector delivery may be only of limited clinical use. The more desirable approach is to directly deliver active siRNAs. We describe the use of hydrodynamic administration as a technique to deliver naked siRNA constructs into experimental animals as a method of transient gene knockdown. This approach demonstrates that RNAi can be used to silence endogenous genes, involved in the cause of human diseases, with a clinically acceptable formulation and route of administration.