With the ability to precisely target genes and proteins, oligonucleotide therapeutics have enormous potential in the fight against some of the most challenging diseases of our time, presenting new avenues to reach previously difficult targets. Unlike conventional therapies, these short sequences of chemically synthesized DNA or RNA can bind with high specificity to complementary sequences in mRNA or proteins within target cells to modulate gene expression or impede protein function through processes such as RNA interference, ribonuclease-mediated degradation, splicing regulation, non-coding RNA inhibition, gene activation, and programmed genome editing. While the gene and protein expression modulating properties of oligonucleotides was identified in the early 1970s, the last decade has witnessed a huge surge of interest and momentum for therapeutic oligonucleotides. Remarkable advancements in nucleic acid chemistry and cell biology have helped to refine the design and optimization of oligonucleotide therapies as well as their delivery mechanisms. Currently, there are 23 approved oligonucleotide therapeutics in the US with numerous others in pre-clinical studies, showcasing promising prospects for further development.