RNA interference (RNAi) as a mechanism to selectively silence messenger mRNA (mRNA) expression has revolutionized the biological sciences. With the identification and sequencing of the entire human genome complete, RNAi can be harnessed to rapidly develop novel drugs against any disease target. The ability of synthetic small interfering RNA (siRNA) to potently, but reversibly, silence genes in vivo, has made them particularly well suited as a drug therapeutic. Development of therapeutics using siRNA has advanced rapidly, with five different clinical trials ongoing and several more poised to enter the clinic in the coming years. Although challenges remain, delivery represents the main hurdle for faster and broader development of siRNA therapeutics. In this review, a summary of the advances in in vivo siRNA delivery is presented and discussed. Multiple different delivery approaches have demonstrated success ranging from the relative simplicity of direct local administration of saline-formulated siRNA, to liposome- and polymer-based nanoparticle approaches, to conjugation and complexation approaches. For siRNA therapeutics to achieve their full potential as a revolutionary class of drug molecules, multiple distinct delivery technologies will likely be needed, with selection of delivery approach being dependent on the nature of the clinical indication, the route of administration to be used, and the cell types to be targeted. Lastly, a status report on current clinical trials using siRNA is given.