The use of mutant mouse models of neurodevelopmental and neurodegenerative disease is essential in order to understand the pathogenesis of many genetic diseases such as fragile X syndrome and fragile X-associated tremor/ataxia syndrome (FXTAS). The choice of which animal model is most suitable to mimic a particular disease depends on a range of factors, including anatomical, physiological, and pathological similarities; presence of orthologs of genes of interest; and conservation of basic cell biological and metabolic processes. In this chapter, we will discuss two mouse models of the fragile X premutation which have been generated to study the pathogenesis of FXTAS and the effects of potential therapeutic interventions. Behavioral, molecular, neuropathological, and endocrine features of the mouse models and their relation to human FXTAS are discussed.