Huntington disease (HD) is one of at least nine polyglutamine disorders caused by a CAG expansion in the coding region of a disease-causing gene. These disorders are characterized by selective degeneration of different regions of the brain, which is not explained by the expression pattern of the mutant protein. In HD, degeneration primarily occurs in the striatum and cortex. To examine the mechanisms responsible for the selective neuronal loss in HD, we have generated yeast artificial chromosome (YAC) transgenic models of HD that express full length mutant huntingtin (htt) from a YAC. These mice have appropriate tissue-specific and temporal expression of mutant htt and accordingly recapitulate the motor deficits, cognitive impairment and selective degeneration of HD. As in human patients, mutant htt expression is not increased in the affected regions of the brain. In contrast, detection of mutant htt in the nucleus is earliest and greatest in the striatum, the region most affected in HD, suggesting that selective nuclear localization of mutant htt may contribute to the region specific atrophy in these mice. Selective phosphorylation of mutant htt on serine 421 may also contribute, as phosphorylation of mutant htt reduces its toxicity and is decreased in the striatum compared to other regions of the brain. Finally, the fact that mutant htt expression increases the susceptibility of striatal neurons to excitotoxicity but not neurons from the cerebellum, suggests that altered sensitization to excitotoxic death may also contribute to selective degeneration in YAC mice. Overall, YAC mice recapitulate the region specific damage that occurs in HD and provide a suitable model for examining the mechanisms underlying of selective degeneration.