The main barrier to the use of RNAi in mammalian systems is the difficulty in delivering siRNA or shRNA to the appropriate tissues. Although progress has been made in this area, many of the technologies developed require specialized expertise and reagents that are beyond the reach of most investigators. In contrast, the hydrodynamic injection technique is simple to perform and enables highly efficient delivery of naked, unmodified siRNA to a number of tissues, especially the liver. This review describes the development of the technique and explores the possible mechanisms that enable uptake of siRNA to biological effect. Examples of the use of hydrodynamic injection in animal models of disease and for the study of gene function are presented and discussed.