RNA interference (RNAi) is a natural mechanism for the modulation of gene expression by small interfering RNAs (siRNAs). A broad range of human diseases, including cancer, metabolic disorders, and neurodegeneration can be treated via the silencing of specific genes using siRNAs. Early attempts to harness RNAi for therapeutic development focused on lipid- or nanoparticle-formulated, minimally modified siRNAs (reviewed in (1,2)). Recently, non-formulated, conjugate-mediated delivery emerged as an alternative, clinically dominant delivery paradigm. By changing the nature of the ligand, this approach has the potential to enable targeted delivery to a variety of tissues.