•Locked nucleic acid-modified antisense oligonucleotides (LNAs) bind to and modulate RNA.•The high binding affinity of LNAs significantly improves potency.•Structural diversity of LNAs profoundly impact many drug properties besides potency.•Harnessing this diversity offers new opportunities for discovering LNA-based drugs. Over the past 20 years, the field of RNA-targeted therapeutics has advanced based on discoveries of modified oligonucleotide chemistries, and an ever-increasing understanding of how to apply cellular assays to identify oligonucleotides with improved pharmacological properties in vivo. Locked nucleic acid (LNA), which exhibits high binding affinity and potency, is widely used for this purpose. Our understanding of RNA biology has also expanded tremendously, resulting in new approaches to engage RNA as a therapeutic target. Recent observations indicate that each oligonucleotide is a unique entity, and small structural differences between oligonucleotides can often lead to substantial differences in their pharmacological properties. Here, we outline new principles for drug discovery exploiting oligonucleotide diversity to identify rare molecules with unique pharmacological properties. LNA-modified antisense oligonucleotides (LNAs) are widely used in RNA therapeutics. The structural diversity of LNAs affects most drug properties. Exploiting this diversity offers new opportunities for discovering LNA-based drugs.