Even 135 years after it was first described, Amyotrophic lateral sclerosis (ALS), remains intractable, with no known cure and only a single FDA approved therapy, the sodium channel blocker, riluzole. More commonly known as Lou Gehrig’s disease, ALS is a rapidly progressive, adult-onset neurodegenerative disorder characterized by selective dysfunction and destruction of motor neurons in the brain and spinal cord, resulting in paralysis and subsequent fatality within 3-5 years of the first appearance of symptoms (Bruijn et al. 2004) remains the most common but yet one of the most elusive motoneuron diseases; despite decades of targeted experimental and clinical research and the identification of numerous potential putative cellular mechanisms, its complete etiology remains unknown. We contend that the lack of a comprehensive view of the complete pathophysiology of ALS has likely been the single largest hindrance to the development of successful treatment strategies. To this end, we are constructing relational models of this system in an effort to examine the potential for combination treatment strategies.