 RNA interference, RNAi, an evolutionary conserved mechanism for post-transcriptional gene regulation has recently advanced towards clinical trials. However, the successful translation of RNAi into clinically viable treatments requires the development of safe and effective delivery systems. Nanotechnology-based delivery systems offer promising solutions to address the challenges associated with RNAi delivery. This review focuses on the major hurdles in achieving efficient RNAi delivery and highlights recent advancements in nanotechnology-based delivery systems for targeted RNAi therapeutics. This article was authored by John C. Burnett, John J. Rossi, Jojo, and others.