Despite numerous reports demonstrating mitochondrial abnormalities associated with amyotrophic lateral sclerosis (ALS), the role of mitochondrial dysfunction in the disease onset and progression remains unknown. The intrinsic mitochondrial apoptotic program is activated in the central nervous system of mouse models of ALS harboring mutant superoxide dismutase 1 protein. This is associated with the release of cytochrome-c from the mitochondrial intermembrane space and mitochondrial swelling. However, it is unclear if the observed mitochondrial changes are caused by the decreasing cellular viability or if these changes precede and actually trigger apoptosis. This article discusses the current evidence for mitochondrial involvement in familial and sporadic ALS and concludes that mitochondria is likely to be both a trigger and a target in ALS and that their demise is a critical step in the motor neuron death.