Recent advances in RNA interference (RNAi) delivery and chemistry have resulted in the development of more than 20 RNAi-based therapeutics, several of which are now in Phase III trials. The most advanced clinical trials have utilized modifications such as lipid nanoparticles and conjugation to N-acetyl galactosamine to treat liver specific diseases. Recent reports have suggested that reducing endogenous oxalate synthesis by RNAi may be a safe and effective therapy for patients with the rare disease, Primary Hyperoxaluria (PH). Our current understanding of endogenous oxalate synthesis indicates that two enzymes, hydroxyproline dehydrogenase and glycolate oxidase (GO), are suitable targets for oxalate reduction therapy. Our studies in a mouse model of PH type 1 have demonstrated that reducing the expression of either of these enzymes in the liver with RNAi significantly reduces urinary oxalate excretion. Early human phase clinical trials are now under way in PH1 patients with RNAi targeting GO. Future elaboration of other contributors of stone disease and improvement in tissue specific targeting with RNAi may lead to further therapies that target idiopathic stone disease.