Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease characterized by progressive degeneration of motor neurons, leading to excessive weakness and paralysis and eventually death of the patient. To date, there is no cure for the disease and a single treatment option is available, which extends life by only couple of months. By the time of symptom onset, the majority of motor neurons (70%-80%) have already degenerated. Importantly, motor neurons exhibit numerous changes in their cellular properties with opposing effects on the cell excitability. This dynamic interaction between disease and compensatory changes allows the motor neuron to maintain a pseudo-normal net excitability that masks disease progression. This talk presents how computer simulations of motor neurons that include the cellular changes help in understanding the excitability regulation of motor neurons during the disease; thereby, revealing potential drug targets for treatment.