RNA interference (RNAi) represents a primeval biological process initially evolved as a defense mechanism against external genetic elements. This pathway can selectively silence any gene associated with disease through a sequence-specific mechanism, positioning small interfering RNAs (siRNAs) as a potent therapeutic tool. Over the past two decades, this concept has transitioned from discovery to clinical application, culminating in the approval of two siRNA-based drugs by Alnylam Pharmaceuticals: ONPATTRO® (Patisiran) and GIVLAARI™ (Givosiran). These approvals mark a significant milestone in the annals of pharmaceutical history, introducing a new paradigm in the treatment and management of diseases. Unlike traditional small molecules and antibodies which needed constant administration, siRNA therapeutics can be administered in a lesser regime (i.e., monthly, quarterly or even bi-annually); while maintaining therapeutic efficacy. The development of siRNA therapies, however, has faced formidable challenges. Nevertheless, one of the key obstacles for siRNA delivery to specific target tissues include developing efficient and safe methods, creating robust nanoplatform for siRNA encapsulation, and optimizing the activity, stability, specificity, all while minimizing potential their off-target effects. This chapter delves into the biogenesis and function of siRNAs, providing a comprehensive overview of the landscape. Additionally, we explore the latest advancements in siRNA delivery platforms that are clinically explored and commercially available, discussing the core principles behind their design.