<p>Oligonucleotide therapeutics are becoming representatives of the “Third Wave” of pharmaceutical innovation, expending from initial rare diseases to oncology and chronic indications, following small molecules and proteins. Globally, hundreds of clinical trials are currently underway, in addition to the 26 oligonucleotide drugs that have already been approved. Although nearly thirty years have elapsed since the initial approval of Fomivirsen, oligonucleotide therapeutics continue to pose unique CMC (Chemistry, Manufacturing, and Controls) challenges that are distinct from small molecules. Furthermore, the lack of harmonized ICH guidelines specifically for oligonucleotides forces developers to navigate a “regulatory grey area” between new molecular entities (NMEs) and biologics. This perspective focuses on the technical and regulatory hurdles of API (Active Pharmaceutical Ingredient) CMC development, covering synthesis (including conjugation strategies with delivery systems), analysis and regulatory aspects, with a specific emphasis on stage-appropriate requirements from the Investigational New Drug (IND) application to the New Drug Application (NDA).</p> Graphical Abstract <p></p>