Human preterm infants are at risk to develop cerebral palsy, cognitive or behavioural impairments. The most recognized underlying brain lesion in preterms is periventricular white matter damage (WMD) which can be focal, multifocal or diffuse. Periventricular leukomalacia is the best described type of periventricular WMD. Clinical, epidemiological and experimental studies have allowed demonstrating the multifactorial origin of these WMD in preterms, generating more than one potential target for neuroprotection. These studies have permitted to unravel some key factors such as inflammation and excess production of cytokines, oxidative stress, hypoxic-ischemic insults, excess release of glutamate and the excitotoxic cascade. Animal models have also revealed that pre-oligodendrocytes, macrophages-microglia and sub-plate neurons are key cells in the pathophysiology of periventricular WMD. One key safety issue for potential neuroprotective strategies in premature newborns is the demonstration of the lack of interference with normal brain development. Several neuroprotective approaches are currently tested in animal models of WMD, including drugs targeting glutamate receptors, drugs targeting inflammation, cytokines or macrophage activation, antioxidant molecules, and strategies such as growth factors and cell replacement aiming at improving post-lesional plasticity and tissue repair. Finally, some clinical trials using magnesium sulfate in preterms have been completed or are in progress.