Human neurodegenerative diseases, like Alzheimer’s, Parkinson’s and Huntington’s disease, are late-onset progressive disorders for which few cures or treatments are available. Developing new approaches to the understanding and treatment for these diseases takes innovative new approaches. To develop new approaches, we are using a very simple, but powerful genetic system, Drosophila melanogaster. Drosophila has a complex nervous system, and shows complex behaviors like learning and memory. Importantly, key pathways are highly conserved between flies and humans, indicating that we can use flies to define genes and pathways of relevance to humans. In our studies we express the human disease gene in the fly to recreate the disease, and then take advantage of powerful genetic approaches in the fly to define modifiers and mechanisms. These studies have revealed new insight in human disease, and the foundation for new approaches modulate disease progression.