Chronic low back pain caused by intervertebral disc (IVD) degeneration, also termed chronic discogenic low back pain (CD-LBP), is one of the most prevalent musculoskeletal diseases. Degenerative processes in the IVD, such as inflammation and extra-cellular matrix breakdown, result in neurotrophin release. Local elevated neurotrophin levels will stimulate sprouting and innervation of sensory neurons. Furthermore, sprouted sensory nerves that are directly connected to adjacent dorsal root ganglia have shown to increase microglia activation, contributing to the maintenance and chronification of pain. Current pain treatments have shown to be insufficient or inadequate for long-term usage. Furthermore, most therapeutic approaches aimed to target the underlying pathogenesis of disc degeneration focus on repair and regeneration and neglect chronic pain. How biomolecular therapies influence the degenerative IVD environment, pain signaling cascades, and innervation and excitability of the sensory neurons often remains unclear. This review addresses the relatively underexplored area of chronic pain treatment for CD-LBP and summarizes effects of therapies aimed for CD-LBP with special emphasis on chronic pain. Approaches based on blocking pro-inflammatory mediators or neurotrophin activity have been shown to hamper neuronal ingrowth into the disc. Furthermore, the tissue regenerative and neuro inhibitory properties of extracellular matrix components or transplanted mesenchymal stem cells are potentially interesting biomolecular approaches to not only block IVD degeneration but also impede pain sensitization. At present, most biomolecular therapies are based on acute IVD degeneration models and thus do not reflect the real clinical chronic pain situation in CD-LBP patients. Future studies should aim at investigating the effects of therapeutic interventions applied in chronic degenerated discs containing established sensory nerve ingrowth. The in-depth understanding of the ramifications from biomolecular therapies on pain (chronification) pathways and pain relief in CD-LBP could help narrow the gap between the pre-clinical bench and clinical bedside for novel CD-LBP therapeutics and optimize pain treatment.