Amyotrophic lateral sclerosis is a devastating neurodegenerative disease whose etiology remains poorly understood. Since the genetic basis of disease is known in only a small subset of cases, there has been substantial interest in determining whether environmental factors act as triggers of ALS. Viruses have received longstanding attention as potential ALS triggers. Yet, existing studies have not provided a compelling case for causation. This review summarizes the evidence supporting a link between viral infection and motor neuron disease, with a focus on ALS. Limitations of prior studies are discussed and contextualized, and recent work that has provided stronger mechanistic evidence for viruses in disease pathogenesis is highlighted. Finally, we offer a new perspective on the association of viruses with ALS, and underscore the need for multidisciplinary approaches bridging neurology and infectious diseases research to move the field forward in the future.