DNA is a critical component in the storage and replication of genetic information in living organisms. The building blocks of DNA, nucleosides, form stable, selective pairs (GC and AT) between complementary, single-stranded DNA polymers to give rise to a stable secondary helical structure. Well documented are the forces bringing these base pairs together selectively: hydrogen bonding, base-stacking, complementary shape, etc. However, increasing interest and utility in both biophysical assays (PCR and other hybridization techniques) and expansion of the genetic alphabet to beyond simply four base pairs, have led chemists to synthesizing a library of non-natural nucleosides to study their impact on the stability of DNA duplexes. This research attempts to answer the ongoing questions: what are the rules governing stability of non-natural nucleosides in DNA? Are there other weak, non-covalent interactions which can be exploited for stabilizing DNA duplexes?Initial research was centered around the design and synthesis of universal bases in DNA. A universal base is a non-natural nucleoside which can pair non-selectively with each of the four natural nucleobases in DNA duplexes. These residues are important in hybridization-based detection techniques where the target sequence is not completely known. Among the most widely used universal bases is 5-nitroindole, though little research has gone into what impact other functional groups at that position may have on universality of the residue. Here, a set of nine unique 5-substituted indoles were synthesized and inserted into DNA oligomers to be screened as universal bases and compared to 5-nitroindole. The results showed that, while drawing any conclusive trend was difficult, there are functional groups other than nitro which dramatically increase the universality and stability of non-natural residues.Next, a series of substituted phenyl non-natural nucleosides designed to have very high dipole moments were synthesized and tested as universal bases and non-canonical base pairs in DNA duplexes. The former continues efforts to discover nucleobase replacements that nonselectively recognize all four Watson-Crick bases with a minimal destabilization of the duplex structure. The latter application involves the development of new selective base pairs to expand the information could be stored in a DNA polymer both in vivo and in vitro. The results showed that these residues are less universal and slightly more selective than the substituted indoles of the previous study, though one residue destabilizes the DNA duplex to a lesser degree. As novel base pairs, the substituted phenyl nucleosides made stronger self-pairs and cross-pairs in DNA duplexes than they did when paired with the canonical bases. This suggests that a highly polarized phenyl core may present a useful scaffold for future design of stable, novel base pairs. Lastly, an investigation into the possible stabilizing forces of halogen bonding in DNA duplexes. Halogen bonding is an electrostatic interaction analogous to hydrogen-bonding which permits a halogen to behave as a Lewis acid. A series of halogenated phenyl non-natural nucleosides were synthesized and paired with other substituted phenyl and pyridyl residues containing Lewis basic sites (NO2, OCH3, and N) to determine the extent to which halogen bonding could stabilize a DNA duplex. Further optimization of the geometry and spacing of the halogen bonding interaction led to several base pairs which appeared to gain an appreciable amount of stability from a constructive halogen bonding interaction.