In MS lesions, an initial episode of transient demyelination may be followed by spontaneous remyelination. However, remyelination typically fails with recurring or chronic myelin damage. The current studies show the advantages of the cuprizone model of chronic demyelination for focusing on this compromised repair response. Importantly, our analysis in FGF2 j/j mice demonstrates that it is possible to overcome chronic lesion effects on endogenous oligodendrocyte lineage cells to increase remyelination. More specifically, taken together with our previous work (11, 12) , our findings in FGF2 j/j mice indicate that removing FGF2 inhibition of OP differentiation promotes spontaneous remyelination from a depleted pool of endogenous progenitors that persists after chronic demyelination.