Amyotrophic lateral sclerosis (ALS) is a motor neuron disease whose pathophysiological deficits causing impairment in motor function are largely unknown. Recently, our group has found significant high levels of H2S in the liquor of 37 ALS sporadic patients and in tissues and media from the spinal cord cultures bearing the familial ALS (fALS) mutation SOD1G93A (Davoli et al., 2015). Hydrogen sulphide (H2S) has been considered a physiological messenger alike the gasotransmitters nitric oxide and carbon monoxide as well as a novel neuromodulator exerting neuroprotective effects in the brain. Experimentally it is evident that the effect of H2S on the cellular homeostasis depends on its concentration. We propose H2S as a new/additional player in the mechanisms of non-cell-autonomous motor neuron death as a product of glial activation. Here we further discuss its potentials as a novel therapeutic target in ALS.