Huntington disease (HD) is an adult-onset neurodegenerative disease caused by a CAG expansion in the HTT gene. HD is characterized by striatal atrophy and is associated with motor, cognitive and psychiatric deficits. In the presence of the HD mutation, the interactions between huntingtin (HTT) and huntingtin interacting protein 14 (HIP14 or DHHC17) and HIP14-like (DHHC13, a HIP14 orthologue), palmitoyl acyltransferases for HTT, are disturbed, resulting in reduced palmitoylation of HTT. Genetic ablation of either Hip14 or Hip14l recapitulates many features of HD, including striatal atrophy and motor deficits. However, there are no changes in palmitoylation of HTT in either mouse model and, subsequently, the similarities between the phenotypes of these two mouse models and the HD mouse model are believed to result from underpalmitoylation of other HIP14 and HIP14L substrates. HTT acts as a modulator of HIP14 activity such that in the presence of the HD mutation, HIP14 is less active. Consequently, HIP14 substrates are less palmitoylated, leading to neuronal toxicity. This suggests that altered HIP14–HTT and HIP14L–HTT interactions in the presence of the HD mutation reduces palmitoylation and promotes mislocalization of HTT and other HIP14/HIP14L substrates. Ultimately, HD may be, in part, a disease of altered palmitoylation.