RNAi-based drug design has evolved significantly since its discovery, with siRNA therapies now in clinical use for liver-targeted diseases. siRNAs can specifically silence therapeutic targets with high potency and durability, but challenges in delivery remain. The success of siRNA drugs like patisiran and givosiran highlights the importance of chemistry, delivery strategies, and target selection. Key advancements include chemical modifications such as 2'-OMe, 2'-F, and PS to enhance stability and reduce toxicity. The use of lipid nanoparticles (LNPs) for liver delivery has been pivotal, while other delivery methods are being explored for extrahepatic tissues. siRNA design must balance efficacy, safety, and target specificity, with ongoing research into improved chemistries, scaffold optimization, and delivery systems. Informatics plays a crucial role in predicting siRNA functionality and specificity. The future of RNAi-based drugs lies in refining these aspects to expand therapeutic applications beyond the liver.RNAi-based drug design has evolved significantly since its discovery, with siRNA therapies now in clinical use for liver-targeted diseases. siRNAs can specifically silence therapeutic targets with high potency and durability, but challenges in delivery remain. The success of siRNA drugs like patisiran and givosiran highlights the importance of chemistry, delivery strategies, and target selection. Key advancements include chemical modifications such as 2'-OMe, 2'-F, and PS to enhance stability and reduce toxicity. The use of lipid nanoparticles (LNPs) for liver delivery has been pivotal, while other delivery methods are being explored for extrahepatic tissues. siRNA design must balance efficacy, safety, and target specificity, with ongoing research into improved chemistries, scaffold optimization, and delivery systems. Informatics plays a crucial role in predicting siRNA functionality and specificity. The future of RNAi-based drugs lies in refining these aspects to expand therapeutic applications beyond the liver.