Since the first unequivocal description of RNA interference (RNAi) in 1998, it 
has remained one of the hottest topics under investigation, culminating in the 
award of a Nobel Prize to its discoverers in 2006. Excitement over this 
technique derives from the ease with which it can be used to switch-off a 
specific gene in almost any organism, thereby allowing the role of that gene to 
be identified. More importantly, it offers the potential to treat certain 
diseases by switching-off the causative genes. Key to the RNAi pathway are the 
small-interfering RNAs (siRNAs), which at 21-23 nucleotides in length are very 
amenable to analogue development by chemists. However in comparison to the use 
of oligonucleotides as antisense agents, an area where many chemists first 
developed an interest in nucleic acids, the RNAi pathway is exceedingly complex. 
The literature is also complicated by the fact that the phenomenon has been 
studied in a wide range of organisms. In this tutorial review we have presented 
the subject from a more chemical perspective, incorporating a glossary to give a 
clear explanation of the specialist terms. However, the coverage of the biology 
remains sufficiently detailed to give the reader the necessary insight that we 
believe will be essential for the successful design of chemically modified 
siRNA.