Nucleic acids are the most basic molecules of life, storing and transmitting genetic information in all living organisms. To enhance nucleic acid programmability, stability, and function, the fundamental building blocks of DNA and RNA are commonly modified. Furthermore, the ease of synthesis of nucleic acids functionalized at any nucleobase, sugar, or phosphate site, as well as the ability of modifications to impact base pairing, chemical stability, conformation, and interactions with proteins, has led to the development of a wealth of unique modifications with far-reaching applications from drugs and vaccines to nanomachines. Unfortunately, the lack of known structure–function relationships for a range of modified nucleic acids raises questions such as how modifications improve organism survival and how modifications can be used to their full potential in medicine and biotechnology. Computational chemistry provides a valuable tool to gain insights necessary to understand the chemistry of modified nucleic acid building blocks, serving as a powerful predictor of experimental outcomes and clarifying discrepancies between experimental hypotheses and results. This talk will highlight research conducted by high school students, undergraduate students, graduate students, and postdoctoral fellows that uses a range of computational techniques to shed light on the biological implications and design of modified nucleic acids.