Huntington's disease is due to the mutation of the IT15 gene coding for Huntingtin protein (Htt). This mutation leads to the expression of an abnormal repeat of polyglutamines in the N-terminal region of Htt. The pathophysiology of Huntington's disease remains to be elucidated. Various mechanisms have been proposed to account for neuronal dysfunction and death, and include both a gain of toxic function of the mutated Htt and a loss of function of the wild type Htt. Among these mechanisms, transcriptional dysregulation, mitochondrial dysfunction, increased excitotoxicity, as well as alteration of neuritic transport and synaptic transmission have been proposed. Interestingly, there is a prominent vulnerability of the striatal neurons, despite the ubiquitous expression of Htt. This may be due to the particular morphological and functional characteristics of these neurons, or to their location within the cerebral networks and the inputs they receive. As multiple mechanisms are involved in neuronal death, the use of drugs association should be considered in future neuroprotective therapeutic trials.