The loss of central nervous system myelin and the failure of remyelination by oligodendrocytes contribute to the functional impairment that characterizes diseases such as multiple sclerosis. Why myelin repair fails in multiple sclerosis is currently unclear; however, new understanding of the generation of oligodendrocytes and myelination during development, as well as an increasing understanding of the bases of successful remyelination, are providing new insights and therapeutic targets. We propose that successful myelin repair of the adult CNS recapitulates a sequence of stages that generally correlate with those seen during development, whereas unsuccessful myelin repair results from the perturbation of a critical process in any one of several sequential events. Defining the rate-limiting steps and most vulnerable aspects at each stage of myelin repair will provide logical targets for therapeutic intervention in demyelinating diseases such as multiple sclerosis.