Calcium dependent processes have long been implicated in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS), a progressive neurodegenerative disease which leads to death on average after 3-4 years due to painless generalized weakness without sensory loss eventually causing respiratory failure. In histopathology, upper and lower motoneurons die with signs of mitochondrial calcium overload, and fragmentation of the Golgi apparatus and the endoplasmic reticulum (ER) while cytosceletal proteins and misfolded proteins aggregate into intracytoplasmic inclusion bodies. Surrounded by widespread astrogliosis subcortical, intracortical, transcallosal and corticospinal tracts connecting the motor cortex degenerate. Spinal motoneurons retract from the neuromuscular junction and undergo axonal swelling before disintegration. ALS muscle fibres paradoxically seem to increase non-mechanical energy consumption, and liver mitochondria display disruption similar to neuromuscular endplates suggesting a systemic disease process which mainly targets selectively vulnerable motoneurons. In laser-captured spinal human post mortem motoneurons posttranslational editing of the GluR2 subunit of the AMPA receptor was impaired, supporting the notion of chronic calcium dependent AMPA receptor mediated excitotoxicity as one of the cell death mechanisms. The disease spares oculomotor nuclei and Onuf's nucleus which both express high levels of calcium buffering protein in contrast to spinal motoneurons sensitive to the disease process. More recently, intracellular calcium deregulation as key pathway in motoneuron degeneration is being recognized with increased understanding of ER – mitochondria calcium shuttling. 5-10% of ALS patients have a positive family history of mostly autosomal dominant heredity with SOD1 mutations and TDP43 mutations present in a large portion of familial ALS. Mutant SOD1 seems to be displaced into mitochondria causing reduced calcium uptake capacity which in motoneurons reduces the main calcium buffering mechanism. Other effects of mutant SOD1 have been observed on the ER where protein processing seems to become more error prone and chronic calcium depletion of the ER may lead to exhaustion of the protective unfolded protein response (UPR). From these findings the hypothesis of a toxic shift of calcium from the ER to mitochondria within the ER-mitochondria calcium cycle (ERMCC) has been formed which may represent a key signalling pathway in the low calcium buffered motoneurons vulnerable to the ALS pathway. ERMCC modulators may therefore play an important role in treating this devastating disease, and possibly other neurodegenerative diseases like Parkinson's disease and Alzheimer's disease.