To date, studies have demonstrated the dynamic influence of exogenous environmental stimuli on multiple regions of the brain. This environmental influence positively and negatively impacts programs governing myelination, and acts on myelinating oligodendrocyte (OL) cells across the human lifespan. Developmentally, environmental manipulation of OL progenitor cells (OPCs) has profound effects on the establishment of functional cognitive, sensory, and motor programs. Furthermore, central nervous system (CNS) myelin remains an adaptive entity in adulthood, sensitive to environmentally induced structural changes. Here, we discuss the role of environmental stimuli on mechanisms governing programs of CNS myelination under normal and pathological conditions. Importantly, we highlight how these extrinsic cues can influence the intrinsic power of myelin plasticity to promote functional recovery.