Due to high homology to the human genome and rapid development, zebrafish have been successfully used to model diseases of the neuromuscular system. In this seminar, I will present current advances in modeling genetic causes of Amyotrophic Lateral Sclerosis (ALS), the most common motor neuron degeneration and show how epistatic interaction studies in zebrafish have helped elucidate synergistic effects of major ALS genes and their cellular targets.