There is widespread and growing interest in the use of phosphorothioate-modified oligonucleotides as sequence-specific agents to control transcription, splicing, translation and other regulated processes in vitro and in vivo, as pharmaceuticals. These exciting applications are predicated on the resistance of phosphorothioate oligonucleotides to degradation by nucleases, a property that results simply from incorporation of sulfur into the phosphate backbone. The popularity of phosphorothioate oligonucleotide analogs derives from several of their features: relatively easy automated synthesis, uncomplicated purification and handling, plus high solubility in water. Presented here are current preparative and analytical methods, together with a comprehensive comparative analysis of solid-phase and solution processes for manufacturing phosphorothioate oligonucleotides as bulk pharmaceutical compounds for clinical evaluation. A prospective view of the future is offered with the hope of directing attention to important areas of needed research dealing with phosphorothioate oligonucleotide technology in particular, and manufacturing of nucleic acid pharmaceuticals in general.