RNA interference, mediated by small interfering RNAs (siRNAs), is a powerful tool for investigation of gene functions and it is increasingly being used as a therapeutic agent. However, not all siRNAs are equally potent - although simple rules for the selection of good siRNAs were proposed early on, siRNAs are still plagued with widely fluctuating efficiency. Recently, new design tools that incorporate both the structural features of the targeted RNAs and the sequence features of the siRNAs have substantially improved the efficacy of siRNAs. In this chapter, we present the algorithms behind these accessibility-aided tools and show how to design efficient siRNAs with their help.