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The sequelae of disk degeneration are among the leading causes of functional incapacity in both sexes and are a common source of chronic disability in the working years. Disk degeneration involves structural disruption and cell-mediated changes in composition. Mechanical, traumatic, nutritional, and genetic factors all may play a role in the cascade of disk degeneration, albeit to variable degree in different individuals. The presence of degenerative change is by no means an indicator of symptoms, and there is a very high prevalence in asymptomatic individuals. The etiology of pain as the symptom of degenerative disease is complex and appears to be a combination of mechanical deformation and the presence of inflammatory mediators. The role of imaging is to provide accurate morphologic information and influence therapeutic decision making. A necessary component, which connects these two purposes, is accurate natural history data. Understanding the relationship of etiologic factors, the morphologic alterations, which can be characterized with imaging, and the mechanisms of pain production and their interactions in the production of symptoms will require more accurate and reproducible stratification of patient cohorts.