Therapeutic oligonucleotides have emerged as a powerful paradigm with the ability to treat a wide range of the human diseases. As a result, we have witnessed more than one hundred oligonucleotides currently in active clinical trials and eight Food and Drug Administration (FDA)-approved drugs. Until now, the demand for oligonucleotide-based drugs has been fulfilled by conventional solid-phase synthesis in an effective manner. However, there are products in advanced stages of clinical trials projecting a collective demand of metric ton quantities in the near future. Therefore, large-scale manufacturing of these products has become a high priority for process chemists. This article summarizes the advances in liquid-phase oligonucleotide synthesis (LPOS) as a possible alternative strategy to meet the scale-up challenge. A review of the literature describing major efforts in developing LPOS technologies is presented. Gratifyingly, serious attempts are under way to develop an efficient environmentally benign green chemistry protocol that is scalable and cost effective for the manufacturing of oligonucleotides. A summary of the most innovative LPOS protocols has been included to provide a glimpse of what may be possible in the future for large-scale production of oligonucleotides. © 2019 by John Wiley & Sons, Inc.