Depending on individual lesion location and extent, reorganization of the human motor system has been observed with a high interindividual variability. In addition, variability of forces exerted, of motor effort, and of movement strategies complicates the interpretation of functional imaging studies. We hypothesize that a general pattern of reorganization can be identified if a homogeneous patient population is chosen and experimental conditions are controlled. Patients with amyotrophic lateral sclerosis (ALS) and healthy volunteers were trained to perform a simple finger flexion task with 10% of each individual's maximum grip force with constant movement amplitude and frequency. The activation pattern in ALS patients was distinctly different to that in healthy controls: In ALS patients, motor cortex activation was located more anteriorly, encompassing the premotor gyrus. The cluster volume within the supplementary motor area (SMA) was higher and shifted toward the pre-SMA. Contralateral inferior area 6 and bilateral parietal area 40 revealed higher cluster volumes. Our results demonstrate a general pattern of functional changes after motor neuron degeneration. They support the concept of a structurally parallel and functionally specialized organization of voluntary motor control. Degeneration of the first and second motor neurons leads to enhanced recruitment of motor areas usually involved in initiation and planning of movement. Partial compensation between functionally related motor areas seems to be a strategy to optimize performance if the most efficient pathway is unavailable.