Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by the progressive degeneration of upper and lower motoneurons. Despite motoneuron death being recognized as the cardinal event of the disease, the loss of glial cells and interneurons in the brain and spinal cord accompanies and even precedes motoneuron elimination. In this review, we provide striking evidence that the degeneration of astrocytes and oligodendrocytes, in addition to inhibitory and modulatory interneurons, disrupt the functionally coherent environment of motoneurons. We discuss the extent to which the degeneration of glial cells and interneurons also contributes to the decline of the motor system. This pathogenic cellular network therefore represents a novel strategic field of therapeutic investigation.