Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder clinically characterized by intention tremor and gait ataxia, in addition to other conditions including hypothyroidism, autonomic dysfunction, hypertension, peripheral neuropathy, and cognitive decline. FXTAS affects some males (approximately 40%) and in less degree female premutation carriers (8–16%) older than 50 years with an age-dependent symptomatology and penetrance. The CGG repeat number appears to influence the severity and the age of onset of the disorder. The neuropathological hallmark of FXTAS is the presence of eosinophillic, ubiquitin-positive intranuclear inclusions in both neurons and astroglia throughout brain. FXTAS is due to RNA toxicity caused by elevated levels of CGG-expanded mRNA containing 55–200 CGG repeats, which is found in the intranuclear inclusions that sequester various proteins including ubiquitin, αB-crystallin, lamin A/C, hnRNP A2, myelin basic protein, and Sam68. The expression of the expanded CGG repeat FMR1 mRNA also induces a cellular stress response and leads to a disruption of the nuclear lamin A/C architecture. These alterations are observable even in early development, suggesting that the expanded-repeat mRNA triggers pathogenic mechanisms that can provide a molecular basis for the neurodevelopmental abnormalities observed in some children who are carriers of an FMR1 premutation allele. Finally, the presence of cellular dysregulation in older adults who do not present clinical features of FXTAS may suggest that additional genetic or environmental protective factors may play a role in the pathogenesis of FXTAS.