X-linked adrenoleukodystrophy (X-ALD) is a severe inherited neurodegenerative disorder characterized by adrenal insufficiency and graded damage in the nervous system. Loss of function of the peroxisomal ABCD1 fatty-acid transporter, resulting in the accumulation of very long-chain fatty acids in organs and plasma, is the genetic cause. Treatment with a combination of antioxidants halts the axonal degeneration and locomotor impairment displayed by the animal model of X-ALD, and is a proof of concept that oxidative stress contributes to axonal damage. New evidence demonstrates that metabolic failure and the opening of the mitochondrial permeability transition pore orchestrated by cyclophilin D underlies oxidative stress-induced axonal degeneration. Thus, cyclophilin D could serve as a therapeutic target for the treatment of X-ALD and cyclophilin D-dependent neurodegenerative and non-neurodegenerative diseases.