Nucleic acids have emerged as a powerful class of therapeutics. Through simple base pair complementarity, nucleic acids allow the targeting of a variety of pathologically relevant proteins and RNA molecules. However, despite the preliminary successes of nucleic acids as drugs in the clinic, limited biodistribution, inadequate delivery mechanisms, and target engagement remain key challenges in the field. A key area of research has been the chemical optimization of nucleic acid backbones to significantly enhance their "drug-like" properties. Alternatively, this review focuses on the next generation of nucleic acid chemical modifications: covalent biochemical conjugates. These conjugates are being applied to improve the delivery, functionality, and targeting. Exploiting research on heterobifunctionals, such as PROTACs, RIBOTACs, molecular glues, etc., has the potential to dramatically expand nucleic acid drug functionality and target engagement capabilities. Such next-generation chemistry-based enhancements have the potential to unlock nucleic acids as effective and versatile therapeutic agents.