Periventricular leukomalacia is a major neuropathological substrate underlying most of the neurologic morbidity in cerebral palsy. Etiopathogenesis of periventricular leukomalacia is believed to be multifactorial, involving hypoxic-ischemic insults and inflammatory processes. While emphasis was previously placed on hypoxia / ischemia, epidemiological, clinical, experimental and other studies conducted over the last decade have provided evidence for an important role of infective / inflammatory conditions and immune mediators in the pathogenesis of periventricular leukomalacia. Tumor necrosis factor alpha (TNF-a), interleukin-1 beta (IL-1b) and interleukin-2 (IL-2) are overexpressed in affected brains, and receptors for these cytokines are present on many inflammatory and neural cells in the white matter. These findings may be part of a wider network of cytokines, chemokines and other inflammatory factors. There is also evidence for interaction between infective / inflammatory conditions and ischemia / hypoxia as etiopathogenic factors in periventricular leukomalacia / cerebral palsy, as the former may enhance the effects of the latter. These developments in the understanding of the immune responses associated with perinatal brain damage, and the characterization of the implicated cellular and molecular mechanisms may have important implications for neuroprotection strategies aiming at prevention of periventricular leukomalacia and cerebral palsy.