Since the revolutionary discovery of RNA interference (RNAi), a remarkable progress has been achieved in understanding and harnessing gene silencing mechanism; especially in small interfering RNA (siRNA) therapeutics. Despite its tremendous potential benefits, major challenges in most siRNA therapeutics remains unchanged-safe, efficient and target oriented delivery of siRNA. Twenty years after the discovery of RNAi, siRNA therapeutics finally charts its way into clinics. As we journey through the decades, we reminisce the history of siRNA discovery and its application in a myriad of disease treatments. Herein, we highlight the breakthroughs in siRNA therapeutics, with special feature on the first FDA approved RNAi therapeutics Onpattro (Patisiran) and the consideration of effective siRNA delivery system focusing on current siRNA nanocarrier in clinical trials. Lastly, we present some challenges and multiple barriers that are yet to be fully overcome in siRNA therapeutics.