The analysis of naturally occurring mouse mutants with genetic defects in myelin-specific genes has helped to increase understanding of corresponding human neurological diseases. This chapter focuses on one example, the leukodystrophy Pelizaeus—Merzbacher disease (PMD) and a less severe disorder, X-linked spastic paraplegia type 2 (SPG-2). These two diseases are clinically distinct with respect to the degree of hypomyelination and motor dysfunction but involve the same gene encoding myelin proteolipid protein (PLP). Dysmyelination in a natural mouse mutant, termed jimpy, is a model for the connate form of PMD and largely the result of abnormal oligodendrocyte death. In the allelic rumpshaker mouse, a model for SPG-2, oligodendrocytes appear normal in number but fail to assemble myelin correctly. PLP-overexpressing transgenic mice provide experimental evidence that even duplications of the normal PLP gene are not tolerated. A comparison of PLP point mutations with a PLP null allele, generated by gene targeting in mouse embryonic stem cells, demonstrates that dysmyelination and glial cell death are largely abnormal gain-of-function effects caused by aberrant protein expression. The various mutations of the PLP gene illustrate some of the strengths and weaknesses of mouse models for human neurological diseases.