Degenerative disc disease (DDD) is a chronic process that can become clinically manifest in multiple disorders such as idiopathic low back pain, disc herniation, radiculopathy, myelopathy, and spinal stenosis. The limited available technology for the treatment of these and other pathologic and disabling conditions arising from DDD is highly invasive (eg, surgical discectomy and fusion), manifesting a certain degree of complications and unsatisfactory clinical outcomes. Although the precise pathophysiology of DDD remains to be clearly delineated, the progressive decline in aggrecan, the primary proteoglycan of the nucleus pulposus, appears to be a final common pathway. It has been hypothesized that imbalance in the synthesis and catabolism of certain critical extracellular matrix components can be mitigated by the transfer of genes to intervertebral disc cells encoding factors that modulate synthesis and catabolism of these components. The successful in vivo transfer of therapeutic genes to target cells within the intervertebral disc in clinically relevant animal models of DDD is one example of the rapid progress that is being made towards the development of gene therapy approaches for the treatment of DDD. This chapter reviews the ability of gene therapy to alter biologic processes in the degenerated intervertebral disc and outlines the work needed to be done before human clinical trials can be contemplated.