Experimentally induced demyelination due to the direct injection of gliotoxic agents has provided powerful models for studying the biology of remyelination. For the most part, these models have involved injection into white matter tracts of the spinal cord. However, the spinal cord has a number of limitations, such as the size of lesions that it is possible to make and its unsuitability for long-term direct cannulation for the delivery of putative remyelination-enhancing agents. In this study, we describe the natural history of three new models of demyelination/remyelination based on the stereotaxic injection of three gliotoxins: lysolecithin, ethidium bromide, and a combination of anti-galactocerebroside antibody and complement (GalC-ab/comp) into the caudal cerebellar peduncle of adult rats. All three agents produced large areas of demyelination with minimal axonal damage, which undergo extensive remyelination. Ethidium bromide- and GalC-ab/comp-induced lesions remyelinated more slowly than those induced by lysolecithin. The contribution to the remyelination of the lesion by Schwann cells reflects the degree of astrocyte damage incurred within the demyelinated area and is greatest for ethidium bromide-induced demyelination. These new models not only provide further insights into the mechanisms of CNS remyelination but also provide a valuable new resource for addressing a series of key issues relevant to current efforts to promote CNS remyelination either by the enhancement of intrinsic processes or by the transplantation of myelinogenic cells.