Therapeutics based on small interfering RNA (siRNA) have a huge potential for the treatment of disease but requires sophisticated delivery systems for in vivo applications. Lipid nanoparticles (LNP) are proven delivery systems for conventional small molecule drugs with over eight approved LNP drugs. Experience gained in the clinical development of LNP for the delivery of small molecules, combined with an understanding of the physical properties of lipids, can be applied to design LNP systems for in vivo delivery of siRNA. In particular, cationic lipids are required to achieve efficient encapsulation of oligonucleotides; however, the presence of a charge on LNP systems can result in toxic side effects and rapid clearance from the circulation. To address these problems, we have developed ionizable cationic lipids with pKa values below 7 that allow oligonucleotide encapsulation at low pH (e.g., pH 4) and a relatively neutral surface at physiological pH. Further optimization of cationic lipids to achieve maximized endosomal destabilization following uptake has resulted in LNP siRNA systems that can silence genes in hepatocytes at doses as low as 0.005 mg siRNA/kg body weight in mouse models. These systems have been shown to be highly effective clinically, with promising results for the treatment of hypercholesterolemia and transthyretin-induced amyloidosis among others. More LNP siRNA therapeutics, targeting different tissues and diseases, are expected to become available in the near future.