RNA interference (RNAi) offers a powerful method for rapidly identifying specific and potent inhibitors of disease targets from all molecular classes. The major challenge for successful drug development is identifying delivery strategies that can be translated to the clinic. Advances in this area and the commencement of multiple clinical trials with RNAi therapeutic candidates suggest a transformation in modern medicine may soon be realized. This review provides an overview of the molecular mechanism of RNAi, the design of siRNAs and shRNAs, chemical modifications to enhance stability and potency, and strategies for facilitating cellular delivery. Proof-of-concept studies in animal models of human disease demonstrate the broad potential application of RNAi therapeutics. Clinical trials have recently commenced, targeting age-related macular degeneration (AMD) and respiratory syncytial virus (RSV) infection. RNAi therapeutics hold great promise as a new class of drugs that will fill a significant gap in modern medicine.RNA interference (RNAi) offers a powerful method for rapidly identifying specific and potent inhibitors of disease targets from all molecular classes. The major challenge for successful drug development is identifying delivery strategies that can be translated to the clinic. Advances in this area and the commencement of multiple clinical trials with RNAi therapeutic candidates suggest a transformation in modern medicine may soon be realized. This review provides an overview of the molecular mechanism of RNAi, the design of siRNAs and shRNAs, chemical modifications to enhance stability and potency, and strategies for facilitating cellular delivery. Proof-of-concept studies in animal models of human disease demonstrate the broad potential application of RNAi therapeutics. Clinical trials have recently commenced, targeting age-related macular degeneration (AMD) and respiratory syncytial virus (RSV) infection. RNAi therapeutics hold great promise as a new class of drugs that will fill a significant gap in modern medicine.