Low back pain (LBP) is a major cause of disability worldwide that has been linked to intervertebral disc (IVD) degeneration. An improved understanding of the pathogenesis of disc degeneration is now developing, which is leading to the development of a number of possible future therapies targeted at the underlying pathology and regeneration strategies. Although results thus far are promising, the investigation of such therapies in an environment that mimics the mechanical environment of the human disc in vivo is problematic. The development of an in vitro model system that can maintain metabolically active IVD tissue within a loading environment pertaining to that of the human spine is crucial for testing the efficacy of future cell-based and tissue-engineering therapies for IVD degeneration. Here, using our novel loading rig, capable of mimicking the loading environment experienced within the human spine, we have cultured nucleus pulposus tissue explants, applied a daily hydrostatic loading regime for up to 2 weeks and investigated proteoglycan retention, metabolic activity and cellular phenotype. IVD tissue cultured under a loading environment pertaining to the in vivo loading environment maintained metabolic cell activity, proteoglycan content and cellular phenotype. Indeed, all parameters were improved in IVD tissue cultured with load compared to unloaded controls. Such a model is invaluable for investigations assessing the feasibility and efficacy of future therapeutic approaches to inhibiting degeneration or stimulating regeneration of the IVD, where the in vivo loading environment may be crucial to their success or failure.