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This comprehensive review summarizes 1) the synthesis of 4'- thionucleosides with emphasis on their stereoselectivity; 2) the physical and physiological properties of 4'-thionucleic acids; and 3) the applications of 4'- thioRNA for developing functional oligonucleotides. Full details of the stereoselective and practical syntheses of 4'-thioribonucleosides and 2'-deoxy-4'- thionucleosides are described. Since 4'-thionucleic acids have high hybridization and nuclease resistance properties, these modified nucleic acids are expected to be instrumental in the development of a new generation of functional oligonucleotides. Our preliminary studies concerning SELEX and RNAi are also described.