RNA interference (RNAi) is rapidly becoming the method of choice for the elucidation of gene function and the identification of drug targets. As with other oligonucleotide-based strategies, RNAi is envisioned to ultimately be useful as a human therapeutic. Unlike previous nucleic acid therapeutics, small interfering RNAs have the potential to elicit immune responses via interactions with Toll-like receptor 3 and trigger interferon responses like long, double-stranded RNA and its analogs, such as poly(I:C). Recently, the safety of siRNAs has been questioned because they have been shown to trigger an interferon response in cultured cells. We show here that it is possible to administer naked, synthetic siRNAs to mice and downregulate an endogenous or exogenous target without inducing an interferon response.