Recent studies suggest that typical intervertebral disc degeneration is a chronic biologic response to mechanical loading. However, very little is known about the mechanisms underlying this process. We first hypothesized that the mechanism of disc degeneration is a tissue remodeling response to altered tissue stresses induced by excessive static compression. We also hypothesized that dynamic loading, depending on the cycle length, can be beneficial or detrimental to the disc’s health from the perspective of fluid flow driven nutrition. The first hypothesis was addressed through the development of an in vivo mouse model for compression-induced disc degeneration, and the development of a finite element model of the mouse disc which was used to investigate changes in the mechanical environment of the disc in response to static compression. The in vivo mouse model showed, in the inner and middle annulus, disorganization of the collagen fibers, fibrocartilage development, and increased apoptosis. The finite element analysis predicted, in the inner and middle annulus, increased hydrostatic pressure in the solid phase, and loss of tensile strains in the collagen fibers. These results demonstrate that the regions of change in stresses and strains due to static compressive loading correlate with changes in morphology and biological activity in the annulus fibrosus. Furthermore, this correlation is consistent with current tissue remodeling theories and thereby suggests that disc degeneration may be a stress-mediated remodeling response. The second hypothesis was addressed by using a fluid transport model for simulating fluid flow in and out of a disc during dynamic loading. Taking into account the fluid exchange rate and the amount of disc tissue included in this exchange, our results showed that alternating spinal loads every 2 hours is the optimal dynamic loading regimen from the perspective of fluid flow driven nutrition. Alternating less or more frequently adversely affects the fluid flow driven nutrition. In summary, this study provides new insights into how static and dynamic mechanical loading play a role in the mechanisms of disc degeneration and may provide guidance for developing improved occupational guidelines for maintaining disc health and for developing new paradigms for directing disc tissue repair.