The causes of motor neuron death in amyotrophic lateral sclerosis (ALS) are still unknown. Several lines of evidence suggest that mitochondrial dysfunction may be involved in the pathogenesis of ALS. Biochemical and morphological mitochondrial abnormalities have been demonstrated in postmortem spinal cords of ALS patients. Furthermore, in transgenic mice expressing mutant Cu,Zn-superoxide dismutase (SOD1), the antioxidant enzyme associated with familial ALS (FALS), mitochondrial abnormalities precede the disease onset, suggesting that mitochondrial dysfunction is causally involved in the pathogenesis of SOD1-FALS. Despite this evidence, it is not yet fully understood how mutant SOD1 damages mitochondria. Recent work has demonstrated that a portion of mutant SOD1 is localized in mitochondria, both in transgenic mice and in FALS patients, where it forms proteinaceous aggregates. These findings have opened new avenues of investigation addressing the hypothesis that mutant SOD1 may directly damage mitochondria. Major future challenges will be to better understand the mechanisms and the consequences of mitochondrial dysfunction in ALS. If mitochondrial dysfunction is convincingly involved in ALS pathogenesis, either as a primary cause or as contributing factor, it is likely to become a novel target for therapeutic intervention.