3-Nitropropionic acid (3-NPA) is a potent mitochondrial inhibitor that can be administered systemically to create a progressive and localized striatal neurodegeneration mimicking many of the pathological features of Huntington’s disease and other forms of metabolic compromise such as cerebral ischemia, carbon monoxide poisoning, and hypoglycemia. Here we describe a method to produce 3-NPA-induced lesions using the systemically administered toxin. We also describe magnetic resonance imaging methods to allow assessment of lesion severity over time within the same animal.