Amyotrophic lateral sclerosis (ALS) is a progressive adult-onset neurodegenerative disorder characterized by the selective loss of upper and lower motor neurons. Mutations in superoxide dismutase (SOD1) cause about 20 percent of familial ALS which is accompanied by accumulation of misfolded SOD1 onto intracellular organelles. Recently, we identified the 12 kDa macrophage migration inhibitory factor (MIF) as a chaperone for mutant SOD1 which is abundant in non-neuronal tissues. Purified recombinant MIF was shown to directly inhibit mutant SOD1 misfolding and association with mitochondria and ER. Elevating MIF in neuronal cells inhibited the accumulation of misfolded SOD1 and its association with mitochondria and ER, and extended survival of mutant SOD1-expressing motor neurons. Our results revealed that the levels of MIF protein are very low in motor neurons, implicating low chaperone activity as a component of selective vulnerability of motor neurons to mutant SOD1 misfolding and toxicity.