Amyotrophic lateral sclerosis (ALS), which clinically manifests by progressive muscle atrophy and paralysis, is a fatal neurodegenerative disease with patients commonly dying of respiratory failure or pneumonia 3–5 years from initial diagnosis. Currently, the glutamate release inhibitor, riluzole, and recently approved free radical scavenger edaravone are the only medications approved by the FDA for ALS. However, there remains a strong need for new disease‐modifying treatment strategies. Several recent studies suggested possible defects in mitochondrial dynamics in models of ALS, regardless of the causative mutation. However, whether Drp1 hyperactivation and its specific interaction with Fis1 play a role in the pathogenesis of ALS and neurodegeneration of motor neurons and whether its inhibition can reduce ALS pathology are unknown.