During perinatal asphyxia the inflammatory response to tissue injury and the production of cytokines occur after the excitotoxic cascade, at the reperfusion state, as hypoxia upregulates numerous proinflammatory genes of cytokines and chemokines. During perinatal infections CD14 and TLRs expressed on various cells bind to pathogen derived molecules and induce the synthesis of proinflammatory cytokines and chemokines. When the infection is located in uterus these inflammatory mediators enter the fetal circulation by crossing the placenta. Subsequently they cross the blood-brain barrier and cause local inflammation in the fetal brain. In experimental studies as well as in clinical, epidemiologic and neuropathologic studies concerning the newborn infant, an association between perinatal asphyxia and/or infection, cytokines, chemokines and brain damage has been found. In this review we analyse the mechanisms through which proinflammatory cytokines and chemokines may lead to neurodegeneration and brain damage. Particular emphasis is given to the white matter damage of the brain of preterm infants. Preterm infants are more vulnerable to brain damage because of their immature vascular ependymal factors, immature oligodendrocytes and deficient endogenous protective mechanisms. The methods used to modify or block the activity of proinflammatory cytokines and chemokines in order to prevent brain damage are being discussed.