siRNAs are widely used for the control of gene expression in molecular biology and experimental pharmacology. siRNA molecules are the most efficient and specific inhibitors of gene expression to have been discovered, acting at nanomolar and subnanomolar concentrations. Challenges associated with nuclease stability, selecting effective sequences, reducing off-target effects and achieving efficient delivery to target cells and tissues have significantly limited the biomedical applications of siRNA. However, chemical modification is a powerful tool for improving the properties of siRNA. This review examines recent data regarding chemical modifications used to develop potent effectors of gene silencing. The correlation between thermal stability and potency, and between nuclease resistance and duration of the silencing effect, are discussed with relation to chemically modified siRNAs.