A largely historical survey is presented on the development of methods for the synthesis of oligonucleotides containing either 3??-S- or 5??-S-phosphorothiolate linkages. The properties of these modifications are discussed with emphasis on their specific cleavage and the use of a metal ion specificity switch for investigating the role of metal ions in enzyme- catalysed DNA/RNA cleavage processes. Finally, the effect of the 3??-S-phosphorothiolate modification on the structure of nucleic acids is described.