Intervertebral disc (IVD) degeneration remains a clinically important condition for which treatment is costly and relatively ineffective. The molecular basis of degenerative disc disease has been an intense focus of research recently, which has greatly increased our understanding of the biology underlying this process.To review the current understanding of the molecular basis of disc degeneration.Review article.A literature review was performed to identify recent investigations and current knowledge regarding the molecular basis of IVD degeneration.The unique structural requirements and biochemical properties of the disc contribute to its propensity toward degeneration. Mounting evidence suggests that genetic factors account for up to 75% of individual susceptibility to IVD degeneration, far more than the environmental factors such as occupational exposure or smoking that were previously suspected to figure prominently in this process. Decreased extracellular matrix production, increased production of degradative enzymes, and increased expression of inflammatory cytokines contribute to the loss of structural integrity and accelerate IVD degeneration. Neurovascular ingrowth occurs, in part, because of the changing degenerative phenotype.A detailed understanding of the biology of IVD degeneration is essential to the design of therapeutic solutions to treat degenerative discs. Although significant advances have been made in explaining the biologic mediators of disc degeneration, the inhospitable biochemical environment of the IVD remains a challenging environment for biological therapies.