Polyglutamine (PolyQ)-related diseases are dominant late-onset genetic disorders that are manifested by progressive neurodegeneration, leading to behavioral and physical impairments. An increased body of evidence suggests that chromatin structure and epigenetic regulation are involved in disease pathology. PolyQ diseases often display an aberrant transcriptional regulation due to the disrupted function of histone-modifying complexes and altered interactions of the polyQ-extended proteins with chromatin-related factors. In this review we describe recent findings relating to the role of chromatin in polyQ diseases. We discuss the involvement of epigenetic-related factors and chromatin structure in genomic instability of CAG repeats; we describe changes in the expression and regulation of chromatin-related enzymes and in the levels and patterns of histone modifications in disease state; we illustrate the potential beneficial effects of different histone deacetylase (HDAC) inhibitors for the treatment of polyQ diseases, and we end by describing the potential use of human pluripotent stem cells and their differentiated derivatives for modeling polyQ diseases in vitro. Taken together, these accumulating studies strongly suggest that disrupted chromatin regulation may be directly involved with the pathophysiology of polyQ-related diseases.