Nucleic acids are responsible for the storage of genetic information and directly participate in gene replication, transcription and expression, and thereby the control of nucleic acids leads to the regulation of genetic information flow and gene expression. Meanwhile, many non-coding RNAs are in-volved in signal transduction directly. Moreover, nucleic acid-based therapeutic strategies have been lead to drug candidates and are effective tools in drug discovery and disease study at the molecular level as well as the genetic level. Consequently, the 3D crystal structure study and related functional research on natural and unnatural nucleic acids have become very popular area, expanding their potential appli-cation in medicinal and biological chemistry. Since oxygen, sulfur, selenium and tellurium are in the same elemental family (VIA) in the peri-odic table, we anticipate that oxygen atoms in nucleic acids can most likely be replaced with the other chalcogen atoms without causing significant perturbations. Owing to the special K edge and unique properties of selenium, our lab has completed the chemical and enzymatic synthesis of unnatural nucle- ic acids with selenium substitutions at various positions. The selenium functionality in nucleic acid is es-sential for nucleic acids’ structural determination at the atomic level. Additionally this novel elemental feature (atomic size and electronic nature) provides nucleic acids with unique properties. In addition, the selenium derivatization can facilitate crystal growth. Other chalcogen elements are applicable as well to modify nucleic acid, generating some special biofunctions, like the application of phosphorthioate oligonucleotide in gene therapy. This dissertation will outline the chalcogen elements (especially selenium) modifications of nucleic acids, including syntheses strategies, structure studies and potential therapeutic applications. Our research work here tries to show that (1) Selenium functionality is able to facilitate the crystal structure determination, by both helping solve phase problem and accel-erating crystal growth; (2) Selenium functionality can generate special capability to nucleic acids, like improved base pair fidelity, novel atomic interactions and feasibility to be biological chemistry probe; (3) Selenium derivatized oligonucleotides are extraordinary good candidates for gene therapy discovery, considering its stability under nuclease environment. In general, these atom-specific replacements gen-erate a new paradigm of nucleic acids. INDEX WORDS: Nucleic acid, Selenium, X-ray crystal structure, Biofunction, Therapeutics