A recent overview in Nature Biotechnology describes activities of the multiple biotech companies pursuing commercialization of siRNA-based therapeutics. Other than a few cases involving local therapy (intraocular injection for example) most of the projects focused on the liver or on certain solid tumors. The pragmatic reasons for this are very clear. Systemic administration of siRNA almost always requires use of lipid or polymer based nanoparticles to protect the siRNA and to enhance its intracellular delivery. Unfortunately this greatly limits the biodistribution of the siRNA since, in most tissues, standard ~ 100 nm nanoparticles are too big to pass across the endothelial barrier that stands between the blood and parenchymal cells. That leaves the liver and certain rapidly growing tumors where there are gaps or ‘fenestrations’ between the endothelial cells that permit the escape of the nanoparticles from the bloodstream. Thus, like the old apocryphal story about the drunk looking for his wallet under the streetlight, because that’s where the light is, the various biotechs seek siRNA applications in the liver, because that’s where the siRNA goes! Now there are plenty of important diseases that are based in the liver and that may be addressed by siRNA in nanoparticles- that is fine-but what about all the other tissues? Surely there is a need to find ways to deliver siRNA to heart, lungs, other GI organs etc, etc. The biotechs run on short time horizons and need to pursue the path of least resistance in getting siRNA into the clinic. However, it seems that there is a real opportunity here for fundamental research on the extracellular and intracellular transport characteristics of siRNA that could be scientifically interesting and therapeutically relevant.