The glymphatic system is a unique pathway that utilises end-feet Aquaporin 4 (AQP4) channels within perivascular astrocytes, which is believed to cause cerebrospinal fluid (CSF) inflow into perivascular space (PVS), providing nutrients and waste disposal of the brain parenchyma. It is theorised that the bulk flow of CSF within the PVS removes waste products, soluble proteins, and products of metabolic activity, such as amyloid-β (Aβ). In the experimental model, the glymphatic system is selectively active during slow-wave sleep, and its activity is affected by both sleep dysfunction and deprivation. Dysfunction of the glymphatic system has been proposed as a potential key driver of neurodegeneration. This hypothesis is indirectly supported by the close relationship between neurodegenerative diseases and sleep alterations, frequently occurring years before the clinical diagnosis. Therefore, a detailed characterisation of the function of the glymphatic system in human physiology and disease would shed light on its early stage pathophysiology. The study of the glymphatic system is also critical to identifying means for its pharmacological modulation, which may have the potential for disease modification. This review will critically outline the primary evidence from literature about the dysfunction of the glymphatic system in neurodegeneration and discuss the rationale and current knowledge about pharmacological modulation of the glymphatic system in the animal model and its potential clinical applications in human clinical trials.