Pelizaeus-Merzbacher disease (PMD) can now be defined as an X-linked recessive leukodystrophy that is caused by a mutation in the proteolipid protein (PLP) gene on chromosome Xq22. The most common mutation is gene duplication followed in frequency by missense mutations, insertions, and deletions. The clinical spectrum ranges from severe neonatal cases to relatively benign adult forms and X-linked recessive spastic paraplegia type 2. The lack of PLP is accompanied by deficits in the other myelin proteins of the central nervous system, including myelin basic protein, myelin-associated glycoprotein, and cyclic nucleotide phosphodiesterase. Surprisingly, the total absence of PLP due to gene deletion or a null allele causes a relatively benign form of PMD. Abnormal PLP is thought to impair protein trafficking and to induce apoptosis in oligodendroglia. Immunocytochemistry with specific antibodies reveals the PLP deficiency and insufficient generation of myelin sheaths with the remaining proteins. Both excessive biosynthesis of PLP, as in gene duplications, or conformational change of the protein, as in missense mutations, are detrimental to myelination. Several naturally occurring and transgenic animal models with PLP gene mutations or deletions have contributed to our understanding of dysmyelination in PMD and the general knowledge of myelination and myelin repair.