Organic solvent abuse is associated with increased risk for serious medical, neurological, and neuropsychological impairments. While animal research suggests that exposure to organic solvents (especially toluene) may be neurotoxic, much less is known about the consequences of long-term exposure in humans. We reviewed neuroimaging and neuropsychological studies examining chronic toluene misuse in humans. Thirty empirical studies fulfilled the inclusion and exclusion criteria, including case studies (n = 9) as well as group studies with (n = 11) and without a control group (n = 10). Our review indicates that toluene preferentially affects white matter (relative to gray matter) structures and periventricular/subcortical (relative to cortical) regions. The lipid-dependent distribution and pharmacokinetic properties of toluene appears to explain the pattern of MRI abnormalities, as well as the common symptoms and signs of toluene encephalopathy. The commonly observed neuropsychological deficits such as impairments in processing speed, sustained attention, memory retrieval, executive function and language, are also consistent with white matter pathology. We discuss the implications of these findings in the context of a neurodevelopmental framework, as well as the neuropathology and pathophysiology of toluene abuse. We also propose a set of recommendations to guide future research in this area.