Over the past 25 years, the approval of several nucleic acid-based drugs by the US Food and Drug Administration (FDA) has marked a significant milestone, establishing nucleic acid drugs as a viable therapeutic modality. These groundbreaking discoveries are the result of some crucial points in the timeline of nucleic acid drug development. The inventions used in fomivirsen (Vitravene; Isis Pharmaceuticals) development paved the road for structural backbone modifications as well as nucleobase and sugar modifications. The approval of patisiran (Onpattro; Alnylam) demonstrated an effective and safe delivery system for small interfering RNA (siRNA), extending potential applications to other nucleic acids such as messenger RNA (mRNA). Givosiran (Givlaari; Alnylam) further revolutionized the field with a carrier-free, targeted platform, utilizing N-Acetylgalactosamine (GalNAc)-siRNA conjugates to enable efficient delivery, expanding therapeutic applications beyond rare genetic disorders to more common conditions such as hyperlipidemia and hypertension. In this review paper, we highlight the evolution of nucleic acid-based drug development, focusing on the pioneering agents fomivirsen, patisiran, and givosiran, and discuss the ongoing challenges in advancing these therapeutics and vaccines.