Periventricular leukomalacia is a white matter disorder, the neonatal cranial ultrasound images of which predict long-term developmental limitations among preterm infants. The vulnerability of oligodendrocytes has led to the hypothesis that oligodendrocytes suffer the primary damage, with axonal damage occurring as a consequence. In this article, we discuss the differential role of oligodendrocytes and axons in this disorder's etiology, offering analogies from the multiple sclerosis and hydrocephalus literature. We conclude that it is too early to view periventricular leukomalacia exclusively as a consequence of oligodendrocyte damage and/or maldevelopment.