The article reviews the state of siRNA (small interfering RNA) therapeutics, highlighting their potential as a therapeutic modality due to their sequence-specific gene silencing capabilities. After two decades of development, siRNA therapy has achieved significant milestones with the FDA approvals of ONPATTRO™ (patisiran) and GIVLAARI™ (givosiran) by Alnylam Pharmaceuticals. The review discusses the challenges in drug development, such as efficient and safe delivery of siRNAs to target tissues and enhancing their performance in terms of activity, stability, specificity, and off-target effects. It covers the evolution of chemical modifications and delivery platforms, including the GalNAc (N-acetylgalactosamine)-siRNA conjugate, and provides an overview of the latest progress in siRNA therapeutic development. The article also addresses the advantages of siRNA over small molecules and monoclonal antibodies, particularly in treating diseases with no effective treatments available. Finally, it discusses the barriers to siRNA delivery, such as nuclease degradation, immune recognition, and endosomal escape, and reviews various delivery systems like lipid nanoparticles, dynamic polyconjugates, and GalNAc-siRNA conjugates.The article reviews the state of siRNA (small interfering RNA) therapeutics, highlighting their potential as a therapeutic modality due to their sequence-specific gene silencing capabilities. After two decades of development, siRNA therapy has achieved significant milestones with the FDA approvals of ONPATTRO™ (patisiran) and GIVLAARI™ (givosiran) by Alnylam Pharmaceuticals. The review discusses the challenges in drug development, such as efficient and safe delivery of siRNAs to target tissues and enhancing their performance in terms of activity, stability, specificity, and off-target effects. It covers the evolution of chemical modifications and delivery platforms, including the GalNAc (N-acetylgalactosamine)-siRNA conjugate, and provides an overview of the latest progress in siRNA therapeutic development. The article also addresses the advantages of siRNA over small molecules and monoclonal antibodies, particularly in treating diseases with no effective treatments available. Finally, it discusses the barriers to siRNA delivery, such as nuclease degradation, immune recognition, and endosomal escape, and reviews various delivery systems like lipid nanoparticles, dynamic polyconjugates, and GalNAc-siRNA conjugates.