Most neurodegenerative diseases do not cause death of all cells in the nervous system, but rather select groups of cells, whose death or dysfunction leads to the classic phenotypic symptoms that define a particular disease. A fascinating example of enhanced cell-type-specific neurodegenerative disease vulnerability is seen in Huntington’s disease (HD), a monogenic neurodegenerative disease caused by expansion of CAG (glutamine-encoding) trinucleotide repeats in the Huntingtin gene. In HD, medium spiny neurons of the striatum are dramatically affected, and in late stages of this disease, most medium spiny neurons are lost. Eventually, other classes of neurons are also affected in HD, but striatal medium spiny neurons are among the earliest stricken. The enhanced vulnerability of medium spiny neurons cannot be explained merely by the pattern of Huntingtin expression, as the Huntingtin gene itself is expressed in many cells. Thus, medium spiny neurons may express other factors that make them especially susceptible to death in HD (or may fail to express factors that would make them more resistant). Our cell-type-specific studies are aimed at revealing intrinsic differences between medium spiny neurons and other neuronal types that contribute to their enhanced vulnerability in HD.