RNA interference (RNAi) has emerged as a promising therapeutic approach for targeting disease-causing genes. The discovery of RNAi in the 1990s and its subsequent application in mammalian cells in 2001 led to the development of RNAi-based drugs that can specifically silence genes involved in disease. This review discusses the development of RNAi-based therapeutics, from in vitro lead design to in vivo pre-clinical drug delivery and testing. RNAi therapeutics offer a new way to treat diseases by targeting 'undruggable' genes. The mechanism of RNAi involves small interfering RNAs (siRNAs) and microRNAs (miRNAs), which guide the RNAi pathway to silence target genes. siRNAs are particularly effective in gene silencing due to their sequence-specific cleavage of messenger RNA (mRNA), while miRNAs mediate translational repression and mRNA degradation. The development of synthetic siRNAs as drugs is particularly promising due to their consistency and predictability in the RNAi pathway. The process of designing and selecting siRNAs involves bioinformatics design, in vitro studies to determine silencing efficacy, and chemical modifications to improve stability and specificity. siRNAs must be potent, specific, and stable to be effective therapeutics. Off-target effects, such as silencing of genes with partial homology and immune stimulation, must be minimized. Chemical modifications, such as phosphorothioate and 2'-O-methyl, can reduce off-target effects and improve siRNA stability. The delivery of siRNAs is a major challenge in RNAi therapy, with various approaches including direct injection, conjugation to targeting molecules, and liposomal or lipoplex formulations. Successful clinical trials have demonstrated the efficacy of RNAi-based therapeutics in treating diseases such as age-related macular degeneration (AMD) and respiratory syncytial virus (RSV) infection. The development of RNAi-based therapeutics is an exciting area of research with significant potential for future clinical applications.RNA interference (RNAi) has emerged as a promising therapeutic approach for targeting disease-causing genes. The discovery of RNAi in the 1990s and its subsequent application in mammalian cells in 2001 led to the development of RNAi-based drugs that can specifically silence genes involved in disease. This review discusses the development of RNAi-based therapeutics, from in vitro lead design to in vivo pre-clinical drug delivery and testing. RNAi therapeutics offer a new way to treat diseases by targeting 'undruggable' genes. The mechanism of RNAi involves small interfering RNAs (siRNAs) and microRNAs (miRNAs), which guide the RNAi pathway to silence target genes. siRNAs are particularly effective in gene silencing due to their sequence-specific cleavage of messenger RNA (mRNA), while miRNAs mediate translational repression and mRNA degradation. The development of synthetic siRNAs as drugs is particularly promising due to their consistency and predictability in the RNAi pathway. The process of designing and selecting siRNAs involves bioinformatics design, in vitro studies to determine silencing efficacy, and chemical modifications to improve stability and specificity. siRNAs must be potent, specific, and stable to be effective therapeutics. Off-target effects, such as silencing of genes with partial homology and immune stimulation, must be minimized. Chemical modifications, such as phosphorothioate and 2'-O-methyl, can reduce off-target effects and improve siRNA stability. The delivery of siRNAs is a major challenge in RNAi therapy, with various approaches including direct injection, conjugation to targeting molecules, and liposomal or lipoplex formulations. Successful clinical trials have demonstrated the efficacy of RNAi-based therapeutics in treating diseases such as age-related macular degeneration (AMD) and respiratory syncytial virus (RSV) infection. The development of RNAi-based therapeutics is an exciting area of research with significant potential for future clinical applications.