The recent discovery of RNA interference (RNAi) as an efficient and naturally occurring mechanism of gene regulation has revitalized interest in chemically modified RNA analogues. For potential in vivo applications, either in preclinical settings or as therapeutic agents, small interfering RNAs (siRNAs) will require chemical modifications to finetune the thermal stability and increase potency, cellular uptake, and in vivo half-life of the siRNA duplexes. Moreover, chemical modifications may be able to address such difficult and long-standing problems as biodistribution and cell type selective targeting of siRNA. Modern synthetic carbohydrate chemistry is excellently positioned to address the needs of the RNAi community relevant to chemically modified siRNAs. The present article reviews synthesis and properties of sugar-phosphate backbone modifications already used or potentially useful for RNAi applications. Modifications in the sugar moiety only (e.g., 2-O-alkyl and aminoalkyl RNA) and RNA having the entire sugar-phosphate backbone altered (e.g., formacetal and amide-linked RNA) will be discussed. Synthetic routes and biophysical properties of these analogues will be reviewed. Current and potential future applications of modified RNA in fundamental biochemical research and biomedicine, with emphasis on RNA interference, will be briefly discussed.