Degeneration of the intervertebral disc is an important clinical and socio-economic problem. Because of associations between injury rates and physical activity, mechanical factors are thought to play an important role in the incidence and progression of this disease. Bioengineers have historically utilized a strength-of-materials approach to develop tolerance criteria and design interventions meant to reduce injury risk. However, it has become apparent that the disc’s biologic response to loading is an important determinant of degeneration rate. In order to quantify degeneration risk, a hierarchical approach is required which links whole body mechanical exposures to tissue responses that are consistent with the clinical presentation. One challenging aspect of this approach is the definition of accurate constitutive relationships for disc tissues, which are inherently nonlinear, anisotropic and heterogeneous. A second challenge is the development and interpretation of models that allow assessment of the in vivo biologic response to loads. Recent progress in these areas indicates that mechanical and biological factors should be quantitatively linked to provide a comprehensive injury tolerance criteria.