The ability to specifically silence genes using RNA interference (RNAi) has wide therapeutic applications for the treatment of disease or the augmentation of tissue formation. RNAi is the sequence-specific gene silencing mediated by a 21-25 nucleotide double-stranded small interfering RNA (siRNA) molecule. siRNAs are incorporated into the RNA-induced silencing complex (RISC), which mediates mRNA sequence-specific binding and cleavage. Although RNAi has the potential to be a powerful therapeutic drug, its delivery remains a major limitation. The generation of nanosized particles is being investigated to enhance the delivery of siRNA-based drugs. These nanoparticles are generally designed to overcome one or more of the barriers encountered by the siRNA when trafficked to the cytosol. In this review, we will discuss recent advances in the design of delivery strategies for siRNA, focusing our attention to those strategies that have had in vivo success or have introduced novel functionality that allowed enhanced intracellular trafficking and/or cellular targeting. First, we will discuss the different barriers that must be overcome for efficient siRNA delivery. Second, we will discuss the approaches for siRNA delivery by size including direct modification of siRNAs (less than 10 nm), self-assembled particles based on cationic polymers and cationic lipids (100-300 nm), neutral liposomes (<200 nm), and macroscale matrices that contain naked siRNA or siRNA loaded nanoparticles (>100 microm). Finally, we will briefly discuss recent in vivo therapeutic success.