Mutations in Cu/Zn superoxide dismutase 1 (SOD1) have been linked to dominantly inherited forms of amyotrophic lateral sclerosis (FALS). To test the hypothesis that the toxicity of mutant SOD1 originates in Cu(2+)-mediated formation of toxic radicals, we generated transgenic mice that express human SOD1 that encodes disease-linked mutations at two of the four histidine residues that are crucial for the coordinated binding of copper (H46R/H48Q). We demonstrate that mice expressing this mutant, which possesses little or no superoxide scavenging activity, develop motor neuron disease. Hence, mutations in SOD1 that disrupt the copper-binding site do not eliminate toxicity. We note that the pathology of the H46R/H48Q mice is dominated by fibrillar (Thioflavin-S-positive) inclusions and that similar inclusions were evident in mouse models that express the G37R, G85R, and G93A variants of human SOD1. Overall, our data are consistent with the hypothesis that the aberrant folding/aggregation of mutant SOD1 is a prominent feature in the pathogenesis of motor neuron disease.