The fruit fly Drosophila Melanogaster has been widely used to study neurodegenerative diseases. The conservation of nervous system biology coupled with the rapid life cycle and powerful genetic tools in the fly have enabled the identification of novel therapeutic targets that have been validated in vertebrate model systems and human patients. A recent example is in the study of the devastating motor neuron degenerative disease amyotrophic lateral sclerosis (ALS). Mutations in genes that regulate RNA metabolism are a major cause of inherited ALS, and functional analysis of these genes in the fly nervous system has shed light on how mutations cause disease. Importantly, unbiased genetic screens have identified key pathways that contribute to ALS pathogenesis such as nucleocytoplasmic transport and stress granule assembly. In this review, we will discuss the utilization of Drosophila models of ALS with defects in RNA metabolism.