In recent decades the organic solvent toluene (methylbenzene) has emerged as one of the best-studied neurotoxins. Long-term and intense exposure to toluene vapors in humans who abuse spray paint and related substances has led to the recognition that toluene has a severe impact on central nervous system myelin. Chronic toluene abuse produces a devastating neurological disorder, of which dementia is the most disabling component. The clinical syndrome, toluene leukoencephalopathy, can be detected by a combination of characteristic symptoms and signs, detailed neurobehavioral evaluation, and brain magnetic resonance imaging. In this paper, we consider the impact of toluene abuse on our society, describe the specific neurobehavioral deficits in toluene leukoencephalopathy, review the spectrum of neuroimaging findings in patients with this disorder, summarize the teratogenic effects of toluene in both humans and animal models, and offer possible explanations for the range of neuropathological damage seen in brains of individuals who chronically abuse toluene.