Therapeutics based on small interfering RNA (siRNA), which in principle are able to reversibly silence any gene of interest, are under development for the treatment of cancers, viral infections, hereditary disorders and many other diseases. This Review discusses the biological challenges that siRNA delivery materials aim to overcome, as well as the most clinically advanced classes of siRNA delivery systems, including cyclodextrin-polymer nanoparticles, lipid nanoparticles and siRNA conjugates.