Periventricular white matter damage (PWMD) also known as periventricular white matter injury, is one of the major causes of neurological impairment in premature newborns. The etiology of white matter injury is multifaceted with hypoxia-ischemia being an important underlying factor. The developing oligodendrocytes are susceptible to damage resulting in myelination deficits. Excess release of glutamate, free radical production, release of cytokines and iron accumulation are factors thought to mediate damage to the developing white matter. Recent studies have also suggested a role for vascular endothelial growth factor and nitric oxide in the pathogenesis of PWMD. Although the role of microglial cells in the development of PWMD is still debatable, our recent investigations have shed some light on their involvement in the pathogenesis of PWMD. Challenges for the future include in-depth investigation of crosstalk between microglia and immature oligodendrocytes as well as other glial cells and vascular endothelial cells.