The article reviews the evidence that in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and other conditions, the damage is not solely cell autonomous but involves multiple cell types, including non-neuronal cells. The focus is on ALS, particularly cases caused by dominant mutations in Cu/Zn superoxide dismutase (SOD1). The authors highlight that the toxicity of mutant SOD1 can lead to damage in various cell types, such as astrocytes and microglia, which in turn contribute to neuronal dysfunction and disease progression. They discuss eight proposed mechanisms of toxicity, including excitotoxicity, ER stress, proteasome inhibition, mitochondrial dysfunction, extracellular toxicity, superoxide production, axonal disorganization, and microhemorrhages. The article emphasizes that the selective vulnerability of certain neuronal subtypes is due to the convergence of damage from multiple cell types, rather than unique vulnerability within the neurons themselves. This non-cell autonomous mechanism is also discussed in other neurodegenerative diseases, such as Parkinson's disease, Huntington's disease, prion diseases, spinocerebellar ataxias, and Alzheimer's disease, highlighting its broader relevance in neurodegenerative disorders.The article reviews the evidence that in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and other conditions, the damage is not solely cell autonomous but involves multiple cell types, including non-neuronal cells. The focus is on ALS, particularly cases caused by dominant mutations in Cu/Zn superoxide dismutase (SOD1). The authors highlight that the toxicity of mutant SOD1 can lead to damage in various cell types, such as astrocytes and microglia, which in turn contribute to neuronal dysfunction and disease progression. They discuss eight proposed mechanisms of toxicity, including excitotoxicity, ER stress, proteasome inhibition, mitochondrial dysfunction, extracellular toxicity, superoxide production, axonal disorganization, and microhemorrhages. The article emphasizes that the selective vulnerability of certain neuronal subtypes is due to the convergence of damage from multiple cell types, rather than unique vulnerability within the neurons themselves. This non-cell autonomous mechanism is also discussed in other neurodegenerative diseases, such as Parkinson's disease, Huntington's disease, prion diseases, spinocerebellar ataxias, and Alzheimer's disease, highlighting its broader relevance in neurodegenerative disorders.