Chemical synthesis has been a major endeavor to create active siRNAs. The downregulation of mRNA by 21-mer double-stranded siRNAs can be improved by using modified nucleotides, especially 2'-O-alkylated ones. Besides the commercially available 2 cent-O-methyl ribosides, 2'-alkyl groups bearing positive charges are especially promising candidates. We have shown that in a proper formulation they are superior to unmodified siRNAs. This may be due to enhanced stability and most probably to a better uptake into the cells.