HD is an autosomal dominant neurodegenerative disorder characterized by involuntary movements, cognitive impairment progressing to dementia, and mood disturbances. The brains of patients show extensive neuronal loss in the striatum, and the cerebral cortex is also affected. The genetic defect causing HD is an expansion of a CAG repeat encoding a polyglutamine stretch in the target protein, named huntingtin. The age of onset of HD is inversely correlated with the size of the expansion. Polyglutamine expansion represents a novel cause of neurodegeneration, which has been shown to be responsible for seven other inherited disorders. The polyglutamine expansion confers a gain of toxic property to the mutated target proteins. Molecular and cellular studies of the brains of patients and of mice models of polyglutamine expansion diseases have led to the identification of abnormal intracellular inclusions representing aggregation of the mutated protein. However, the mechanism whereby such polyglutamine expansion leads to selective neuronal dysfunction and death is still puzzling.