Remyelination, the process by which new myelin sheaths are restored to demyelinated axons, represents one of the most compelling examples of adult multipotent progenitor cells contributing to regeneration of the injured CNS. This process can occur with remarkable efficiency in both clinical disease, such as multiple sclerosis, and in experimental models, revealing an impressive ability of the adult CNS to repair itself. However, the inconsistency of remyelination in multiple sclerosis, and the loss of axonal integrity that results from its failure, makes enhancement of remyelination an important therapeutic objective. Identifying potential targets requires a detailed understanding of the cellular and molecular mechanisms of remyelination. A critical step in achieving effective remyelination is the differentiation of precursor cells into mature oligodendrocytes. In experimental models of demyelinating disease in aged animals, as well as in multiple sclerosis, such differentiation appears to be impaired. This is due, at least in part, to changes in environmental signals governing remyelination. In particular, myelin debris within lesions appears to contain powerful inhibitors of precursor cell differentiation. Efficient removal of myelin debris by macrophages may thus facilitate differentiation and permit successful remyelination of damaged axons. This may represent a promising therapeutic target for promoting remyelination in multiple sclerosis and thus limiting the accumulation of irreversible neurological disability.