Only a few years after their discovery, siRNAs are catching up with ribozymes and antisense oligonucleotides as efficient tools for gene targeting in vitro and, more recently, also in vivo. This includes the exploration of their potential as therapeutics which will lead to the development of siRNA-based therapeutic strategies. Their ultimate success, however, will Figure 4 : Systemic treatment of mice with PEI-complexed HER-2-specific siRNAs leads to reduced growth of subcutaneous SKOV-3 tumor xenografts due to decreased HER-2 expression. In [70] athymic nude mice bearing subcutaneous tumor xenografts were injected IP with 0.6 nmoles HER-2-specific naked (open circles) or PEI-complexed (closed circles) siRNAs 2-3 times per week and tumor sizes were evaluated daily from the product of the perpendicular diameters of the tumors. Mean +/-standard error of the mean (SEM) is depicted and Student's unpaired t test was used for comparisons between data sets ( * * P < .03, * * * P < .01). Differences in tumor growth reach significance at day 5 indicating the antitumoral effects of the PEI-complexed HER-2-specific siRNAs. strongly depend on the development of powerful and feasible siRNA delivery strategies which need to address several issues including the stability/stabilization of siRNA molecules while preserving their efficacy and maintaining their genesilencing activity, an efficient delivery into the target organ(s) as well as a sufficiently long siRNA half life in the organism and particularly in the target organ. Thus, siRNA delivery strategies must provide siRNA protection and transfection efficacy, the absence of toxic and nonspecific effects, they must be efficacious also when using small amounts of siRNAs and must be applicable in various treatment regimens and in various diseases even when this requires to overcome biological barriers after their administration to reach their target tissue or target organ. The research done on DNA-based gene delivery, ribozyme-targeting, and antisense technology will facilitate this process since it already provides a basis of established technologies. This is also true for the complexation of siRNAs with polyethylenimine, which may represent a promising avenue for siRNA applications in vivo. This may eventually lead to novel therapeutic strategies. 