Preterm infants, including some who have sustained intracranial hemorrhage, appear to be at increased risk of lateral ventricular enlargement. Although some occurrences might be due to an impairment of cerebrospinal fluid flow or absorption, many instances of ventriculomegaly without accompanying macrocephaly reflect diffuse white matter damage resulting in diminished (i.e., hypoplastic) white matter or an inadequate density of axons. Perinatally acquired widespread white matter damage is sometimes associated with the focal white matter necrosis. We hypothesize that in some infants both ventriculomegaly and delayed myelination are consequences of disturbances to myelinogenesis that result from an impairment of cells destined to become oligodendroglia or of disturbances to rapidly growing axons. The vulnerability of developing white matter in preterm newborns might, in part, reflect the diminished availability of growth/ survival factors, or a vulnerability to toxins or physiologic perturbations. Awareness that some ventriculomegaly reflects widely distributed white matter damage should prevent overtreatment of what might appear to be hydrocephalus, but is not due to impaired cerebrospinal fluid dynamics. Increased understanding of the phenomena leading to ventriculomegaly related to paucity of white matter should lead to successful efforts to prevent white matter damage in preterm newborns.