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A few siRNA therapeutics have been FDA\u2010approved, such as Onpattro (patisiran) and Leqvio (inclisiran) to treat hereditary transthyretin amyloidosis and primary hypercholesterolemia, respectively. In addition, several others are currently in clinical trials, highlighting the potential of siRNA\u2010based treatment for undruggable targets. siRNA is a double\u2010stranded RNA molecule that has the potential to inhibit gene expression by degrading target mRNA. The siRNA sequence must be precisely designed for effective gene knockdown and to minimize off\u2010target effects. Strategies for designing siRNA to achieve optimal efficacy are presented in this review. We emphasize approaches that promote effective gene knockdown by siRNA. These approaches include preventing off\u2010target RNAi and ensuring incorporation of the intended guide\/antisense strand into RISC for targeted gene knockdown. This review also discusses the assessment of siRNA efficacy in vitro and the design of appropriate nonsilencing controls. Furthermore, the challenges of in vivo applications are identified, and strategies to overcome these challenges, such as siRNA delivery methods, biodistribution, and immunotoxicity prevention, are highlighted. Lastly, nucleotide chemical modifications to the ribose sugar and phosphodiester bonds and their effects on siRNA stability, activity, and interaction with the RISC complex are discussed. 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