Based on our evidence for AMPA receptor dysregulation in embryonic motor neurons of SOD1G93A mice and SOD1-linked ALS patient-derived motor neurons, we propose that aberrant Ca2+-mediated influx and signalling are proximal and key events, leading to downstream consequences such as hyperexcitability, excitotoxicity, ER stress and protein aggregation which may account for selective motor neuron death in ALS. The gene discussed is SOD1; the disease is amyotrophic lateral sclerosis.