Nucleic acid-based therapies have become the third major drug class after small molecules and antibodies. The role of nucleic acid-based therapies has been strengthened by recent regulatory approvals and tremendous clinical success. In this review, we look at the major obstacles that have hindered the field, the historical milestones that have been achieved, and what is yet to be resolved and anticipated soon. This review provides a view of the key innovations that are expanding nucleic acid capabilities, setting the stage for the future of nucleic acid therapeutics.