Nucleic acid-based therapies (NATs) have become an increasingly prominent class of drugs due to the recent clinical successes made possible by nucleic acid chemical modifications. This class of therapies includes reagents that inhibit gene expression (antisense oligonucleotides (ASOs) or RNA interference (RNAi)), modulate gene structure (splice-shifting ASOs), increase protein expression (messenger RNA (mRNA)) or direct specific editing of the mammalian genome (CRISPR/Cas gene editing). Each of these technologies relies on specific combinations of chemically modified nucleic acids to increase drug efficacy, safety, and uptake efficiency in desired cell types. The knowledge gained from years of characterizing the biochemical properties of chemically modified oligonucleotides (ONs) combined with recent regulatory approvals will hopefully accelerate more NATs into the clinic to treat currently undruggable or ultrarare diseases. This review discusses the most employed chemical modifications in each of the aforementioned nucleic acid-based technologies and provides an overview of select publications that have demonstrated milestones and successes in improving ON efficacy and/or mitigating undesired off-target effects. Key innovations in chemical modifications that are expanding clinical capabilities are highlighted, casting a positive light on the future of nucleic acid medicine.