Background: The pathology of primary osteoarthritis (OA) begins with structural cartilage damage, which initiates a self-propagating inflammatory pathway that further exacerbates cartilage deterioration. Current standard of care for knee primary OA involves treating the inflammatory symptoms to manage pain, which includes intra-articular (IA) injections of cortisone, an anti-inflammatory steroid, followed by a series of joint-cushioning hyaluronic acid gel injections. However, these injections do not delay the progression of primary OA. More focus on the underlying cellular pathology of OA has prompted researchers to develop treatments targeting the biochemical mechanisms of cartilage degradation. Purpose: Researchers have yet to develop a United States Food and Drug Administration (FDA)–approved injection that has been demonstrated to significantly regenerate damaged articular cartilage. This paper reviews the current research on experimental injections aimed at achieving cellular restoration of the hyaline cartilage tissue of the knee joint. Study Design: Narrative review. Methods: The authors conducted a narrative literature review examining studies on primary OA pathogenesis and a systematic review of non–FDA-approved IA injections for the treatment of primary OA of the knee, described as “disease-modifying osteoarthritis drugs” in phase 1, 2, and 3 clinical trials. Conclusion: New treatment approaches for primary OA investigate the potential of genetic therapies to restore native cartilage. It is clear that the most promising IA injections that could improve treatment of primary OA are bioengineered advanced-delivery steroid-hydrogel preparations, ex vivo expanded allogeneic stem cell injections, genetically engineered chondrocyte injections, recombinant fibroblast growth factor therapy, injections of selective proteinase inhibitors, senolytic therapy via injections, injectable antioxidant therapies, injections of Wnt pathway inhibitors, injections of nuclear factor–kappa β inhibitors, injections of modified human angiopoietin-like–3, various potential viral vector–based genetic therapy approaches, and RNA genetic technology administered via injections.