Although polyglutamine expansion diseases are the most common genetically inherited neurodegenerative disorders, the key pathogenic mechanisms that lead to neuronal cell death are unclear. The expansion of a polyglutamine tract in specific proteins is the defining molecular insult, leading to cell-type and region-specific neuronal death. Intraneuronal aggregates of the affected protein can be found in the nucleus and/or cytoplasm and are a hallmark of these disorders. Whether and how aggregation leads to pathology, however, is under debate. In this chapter, we will review some of the key observations using Drosophila models of polyglutamine disorders that have highlighted a host of potential contributing pathologies, including defects in transcription, autophagy, and mitochondrial biology. We will also examine how genetic screening approaches have been used in Drosophila to provide insights into potential therapeutic approaches for polyglutamine disorders.