Within the last decade, Drosophila has emerged as a premiere model system for the study of human neurodegenerative diseases, due to the realization that flies and humans share many structurally and functionally related gene families. Development of such disease models in the fly allows genetic approaches to be applied to address specific hypotheses concerning disease progression and to test candidate modifier genes. More recently these fly models have also been used for drug discovery. Here, we describe how to utilize the existing fruit fly models of human neurological disorders to identify small-molecule leads that could potentially be further developed for therapeutic use.