Just as the epigenome, the proteome and the electrophysiological properties of a cell influence its function, so too do its intrinsic mechanical properties and its extrinsic mechanical environment. This is especially true for neurons of the central nervous system (CNS) as long‐term maintenance of synaptic connections relies on efficient axonal transport machinery and structural stability of the cytoskeleton. Recent reports suggest that profound physical changes occur in the CNS microenvironment with advancing age which, in turn, will impact highly mechanoresponsive neurons and glial cells. Here, we discuss the complex and inhomogeneous mechanical structure of CNS tissue, as revealed by recent mechanical measurements on the brain and spinal cord, using techniques such as magnetic resonance elastography and atomic force microscopy. Moreover, ageing, traumatic brain injury, demyelination and neurodegeneration can perturb the mechanical properties of brain tissue and trigger mechanobiological signalling pathways in neurons, glia and cerebral vasculature. It is, therefore, very likely that significant changes in cell and tissue mechanics contribute to age‐related cognitive decline and deficits in memory formation which are accelerated and magnified in neurodegenerative states, such as Alzheimer's disease. Importantly, we are now beginning to understand how neuronal and glial cell mechanics and brain tissue mechanobiology are intimately linked with neurophysiology and cognition. The mechanical properties of brain tissue can influence cell migration, neurogenesis, neurite outgrowth, regeneration and neuronal excitability. The extracellular microenvironment of neurons and glia changes in neurodegenerative disease states and, to a lesser extent, with “healthy ageing.” Understanding how perturbed mechanotransduction signalling influences the biochemistry and physiology of neurons and glia may reveal new drug targets for neurodegenerative disorders.