At least nine inherited neurodegenerative diseases share a polyglutamine expansion in their respective disease proteins. These diseases show distinct neuropathological changes, suggesting that protein environment and protein–protein interactions play an important role in the specific neuropathology. A gain of toxic function as a result of an expanded polyglutamine tract can cause the protein huntingtin to interact abnormally with a variety of proteins, resulting in the complex of neuropathological changes seen in Huntington's disease. Recent studies have identified several huntingtin-interacting proteins that might be associated with the normal function of huntingtin and/or involved in the pathology of Huntington's disease. In this article, we focus on the potential roles of huntingtin–protein interactions in the pathogenesis of Huntington's disease.