White matter, comprising about one half the volume of the human brain, is affected by many environmental insults from infancy to old age. Among the most damaging of these insults are hypertension and traumatic brain injury, but also important are diabetes mellitus, obesity, hyperlipidemia, smoking, metabolic syndrome, unhealthy diet, physical inactivity, sleep disturbance, ischemia, physical inactivity, a variety of toxins, air pollution, infection, critical illness, low educational attainment, lower socioeconomic status. depression, and emotional stress. The deleterious impact of these factors can be observed at any age, but special vulnerability can be postulated early and late in life, as the ontogeny of white matter features maximal volume in the fifth decade. Because schizophrenia most often appears in adolescence and early adulthood, and dementia arises in late life, it can be hypothesized that the early underdevelopment of white matter may predispose to psychosis, while white matter retrogenesis in aging may contribute to the origin of dementias including Alzheimer’s Disease. Substantial evidence indeed exists for white matter pathology, often microstructural, in the pathogenesis of both psychosis and dementia, and a focus of white matter as the site of initial involvement is justified in view of the still poorly understood etiology of these disorders. Moreover, evidence for the importance of white matter inflammation is also accumulating in both psychosis and dementia, perhaps offering a common mechanism to explain how the variety of many diverse white matter insults leads to highly prevalent diseases that have long defied detailed understanding. Finally, a consideration of white matter and the environmental factors that cause its injury implies a major role not only for laboratory efforts to investigate the fundamental pathogenesis of psychosis and dementia, but also for intervention in clinical practice and with public policy to protect white matter health.