In the last years, a large body of studies has been published which describe different strategies for the systemic or local application of siRNAs in vivo. Tables 1-3 give an overview. The probably largest number of papers focuses the use of unmodified siRNAs (Table 1 ) whose administration is often performed IV by hydrodynamic transfection (high pressure tail vein injection). While this method is widely used and in some cases led to efficient target gene inhibition in the liver and, to a lesser extent, in lung, spleen, pancreas, and kidney, it may suffer from certain technical and practical limitations at least in a therapeutical setting since it relies on the rapid IV injection of a comparably large volume (>= 1 ml/mouse/injection, in theory equivalent to a ∼ 3 l IV bolus injection in man). Alternative strategies for the application of naked siRNAs include various delivery routes which, however, often provide an only local administration or rely on an administration at least close to the target tissue or target organ, thus restricting the number of target organs which may not be relevant for certain diseases. It should also be noted that several studies described here and below use rather large amounts of siRNAs and that upon intravenous injection of siRNAs the liver is the primary site of siRNA uptake. As an alternative approach for the application of siR-NAs in vivo, their delivery by liposomes/cationic lipids has been described. For liposome-based siRNA formulations, a wide variety of modes of application allowing local or systemic delivery has been used (Table 2) . Finally, several other strategies for local or systemic siRNA administration have been explored, including chemical modifications of siRNA molecules, electropulsation, polyamine, or other basic complexes, atelocollagen, virosomes, and certain protein preparations (Table 3 ).