White matter disorders are characterized by deficient myelin or myelin loss, lead to a range of neurologic dysfunctions, and can result in early death. Oligodendrocytes, which are responsible for white matter formation, are the first targets for treatment. However, many studies indicate that failure of white matter repair goes beyond the intrinsic incapacity of oligodendrocytes to (re)generate myelin and that failed interactions with neighboring cells or factors in the diseased microenvironment can underlie white matter defects. Moreover, most of the white matter disorders show specific white matter pathology caused by different disease mechanisms. Herein, we review the factors within the cellular and the extracellular microenvironment regulating oligodendrocyte properties and discuss stem cell tools to identify microenvironmental factors of importance to the development of improved regenerative medicine for patients with white matter disorders.