Recent advances in radioimaging and immunocytological techniques have enhanced investigations of neurometabolites and axons, giving rise to renewed interest in human white-matter disorders. A strong correlation between axonal loss and disability in some demyelination diseases (e.g., multiple sclerosis) led to several studies examining the mechanisms of axonal damage. We review the relationship between demyelination, axon loss, and neurologic progression, and the role of advanced neuroimaging in children with different types of leukodystrophies, i.e., X-linked adrenoleukodystrophy, metachromatic leukodysrtophy, Krabbe’s disease, Pelizaeus-Merzbacher disease, and Alexander’s disease.