The intervertebral disc is an avascular, pliant, composite structure that separates spinal vertebrae and, in health, serves to support compression and facilitate movement. Its morphological organization is directed by fluid pressure and consists of a central swelling gel (nucleus), surrounded peripherally by a constraining ligament (annulus fibrosus), and separated from adjacent vertebrae by semi-permeable membranes (endplate). These three tissues serve differing structural roles, are subjected to differing mechanical environments, and are composed of unique matrices and cells. Viewing disc cells as mechanosensors, we use in vivo models of disc loading to identify spatial and temporal relationships between stress/strain and cell function that define normal morphology and drive the architectural changes attributed to normal aging and degeneration. Intra-discal stress patterns consistent with disc health can then be elucidated based on these relationships, and in turn, help us develop spine-loading criteria that parameterize injury tolerance. This same perspective is critical for tissue engineering approaches for disc repair. Cells and matrices meant to guide healing need to withstand the demanding mechanical forces in the acute phases, and differentiate/remodel along the appropriate trajectory in the long-term. Because of their unique potential for adaptation, we are exploring the mechanoplasticity of mesenchymal stem cells (MSCs) and their use in disc repair strategies. Our data demonstrate that these cells respond differentially to pressure and distortion, and can be delivered, retained, and survive in the disc's demanding mechanical/biochemical environment. Because of these features, MSCs are qualified as an intriguing autograft cell type for disc repair.