In vertebrates, the detection of viral nucleic acids is the first step toward innate and subsequent adaptive antiviral immune responses. A sophisticated, protein receptor–based sensor system has evolved to recognize viral nucleic acids and to trigger a variety of antiviral defense mechanisms. The more we learn about this elaborate sensor system, the more it becomes evident how difficult it is to introduce exogenous nucleic acids such as siRNA into cells without triggering antiviral immunoreceptors. In this issue of the JCI, Judge and colleagues provide evidence that siRNA can be designed and delivered in a way that allows specific and successful silencing of target genes in tumor cells in vivo, leading to tumor cell death and prolonged survival of tumor-bearing mice in the absence of immune activation (see the related article beginning on page 661). This study represents a major technological advance, setting new standards for well-controlled siRNA applications in vivo, and has the potential to guide clinical development toward siRNA therapeutics with well-defined and selective gene-silencing activities.