The mechanisms of neurodegeneration in the CAG repeat polyglutamine diseases, including Spinal and Bulbar Muscular Atrophy (SBMA), Huntington's disease (HD), DentatoRubral and PallidoLuysian Atrophy (DRPLA), and Spino-Cerebellar Ataxia (SCA), have been controversial. Issues have included the role of polyglutamine aggregation and possible amyloid formation, localization in the cell nucleus, and possible proteolytic processing. Proposed mechanisms have included activation of caspases or other triggers of apoptosis, mitochondrial or metabolic toxicity, and interference with gene transcription. Recent studies using transgenic mouse and Drosophila models have helped resolve some of these issues and raise hopes for development of therapeutic targets.