The myelin sheath is a multilayered glial membrane that surrounds axons providing insulation and rapid propagation of action potentials and contributing to structural support in both the central nervous system (CNS) and the peripheral nervous system (PNS). Therefore, myelin formation plays a crucial role in maintaining the integrity, connectivity, and functionality of the nervous system, as well as neuronal regeneration after injury or damage. Myelination in early developmental stages requires the molecular and mechanical exogenous cues provided mainly by the axons of the neurons, coupling the myelin-generating oligodendrocytes in the CNS and Schwann cells in the PNS. Complementary to early development, adaptive myelination dynamically regulates myelin remodeling in response to neuronal activity, ensuring optimal synaptic function and plasticity. Adaptive myelination is shown to be extremely mechanosensitive, requiring strict spatial constraints, stiffness, and topography for cell plasticity and myelination. Consequently, myelin regeneration is limited after traumatic injury and in demyelinating neurodegenerative diseases such as multiple sclerosis (MS). In addition to the inflammatory niche created around damaged myelin sheath, it is often overlooked that altered mechanical properties of the surrounding tissue are also pivotal in the inhibition of remyelination. This review focuses on the effects of mechanical cues on the polarization and plasticity of myelin generating cells, as well as on the induction of the myelin sheath during normal development and in pathological conditions. It also aims to give insights into potential mechanoepigenetic therapeutic approaches for demyelinating conditions.