Nucleoside and oligonucleoside dithiophosphates are normal nucleotide and oligonucleotide mimics in which two nonbridging oxygen atoms at a phosphomonoester of a nucleotide or internucleotide phosphate moiety are replaced by two sulfurs. The nuclease resistance properties of nucleoside and oligonucleoside dithiophosphates have made them particularly interesting for the nucleic acid based therapeutics field. The high affinity for certain proteins has drawn some attention from aptamer-based diagnostics and therapeutic applications. The progress of nucleoside and oligonucleoside dithiophosphate development is summarized in this Perspective.