Amyotrophic lateral sclerosis is a fatal adult-onset neurodegenerative disease characterized by progressive muscular weakness and atrophy. The primary feature of amyotrophic lateral sclerosis is the selective loss of motoneurons in the brain and spinal cord. However, changes in synaptic transmission and motoneuron excitability are among the first events that take place during development and accompany the relentless deterioration of motor circuitry. This chapter aims to summarize the current understanding of defects in intrinsic electrophysiological properties of motoneurons, local GABAergic and glycinergic inhibitory as well as cholinergic modulatory interneuron networks, and long-range glutamatergic excitatory input neurons that can precede disease onset or occur during the progression of the disease. We summarize evidence that therapeutic options that target synaptic transmission and intrinsic features of motoneurons might represent novel effective strategies for patients with amyotrophic lateral sclerosis.