Intervertebral disk degeneration is a common and potentially debilitating disease process affecting millions of Americans and other populations each year. Current treatments address resultant symptoms and not the underlying pathophysiology of disease. This has spawned the development of biologic treatments, such as gene therapy, which attempt to correct the imbalance between catabolism and anabolism within degenerating disk cells. The identification of therapeutic genes and development of successful delivery systems have resulted in significant advances in this novel treatment. Continued investigation of the pathophysiology of disk degeneration, however, and safety mechanisms for the application of gene therapy are required for clinical translation.