The fruit fly, Drosophila melanogaster, is an excellent organism for the study of the genetic and molecular basis of metazoan development. Drosophila provides numerous tools and reagents to unravel the molecular and cellular functions of genes that cause human disease, and the past decade has witnessed a significant expansion of the study of neurodegenerative disease mechanisms in flies. Here we review the interplay between oxidative stress and neuronal toxicity. We cover some of the studies that show how proteasome degradation of protein aggregates, autophagy, mitophagy, and lysosomal function affect the quality control mechanisms required for neuronal survival. We discuss how forward genetic screens in flies have led to the isolation of a few loci that cause neurodegeneration, paving the way for large-scale systematic screens to identify such loci in flies as well as promoting gene discovery in humans.