Gene silencing mediated by RNA interference (RNAi) is expected to have a beneficial impact on the treatment of many diseases because of its potency, selectivity and versatility. To maximize the potential of RNAi effectors such as small interfering RNA and microRNA in clinical therapy, the development of a practical delivery system is required, especially for systemic administration. Recent studies demonstrated that chemical modification of these small RNAs and/or encapsulation of them into lipid nanoparticles is a promising strategy to achieve targeted delivery via systemic administration. In this review article, we introduce recent progress of the research on systemic delivery systems for RNAi therapeutics and consider crucial elements for the design of lipid nanoparticles as a small RNA vector.