Short interfering RNAs (siRNAs) represent new potential therapeutic tools, owing to their capacity to induce strong, sequence-specific gene silencing in cells. However, their clinical development requires new, safe, and efficient in vivo siRNA delivery methods. In this study, we report an efficient in vivo approach for targeting gene knockdown in solid tumors by the use of external electric field pulses. We show that gene silencing is efficiently obtained in vivo with chemically synthesized siRNA after targeted electrical delivery in the tumor-bearing mouse. The associated gene silencing was followed on the same animal by fluorescence imaging and confirmed by qPCR. Gene silencing obtained in tumors lasted from 2 to 4 days after a single treatment. Therefore, this method should allow gene function analysis or organ treatment by a localized delivery of siRNAs.