Major advances have been made in recent years in the understanding of the neuropathology and the pathogenesis of the major brain abnormality in premature infants, particularly those born with very low birth weight (VLBW) of< 1,500 g. This abnormality involves both cerebral white matter and neuronal/axonal structures. 1 The importance of this encephalopathy of prematurity is underscored by its key role as substrate for the cognitive/attentional/behavioral/socialization defects experienced by 25 to 50% of VLBW survivors. 2–8 The pathogenesis of the brain abnormality involves an interplay between 2 major initiating insults, hypoxia–ischemia and systemic infection/inflammation. Experimental and clinical data indicate that these insults may operate alone or may potentiate each other. 9–17 A report in this issue of the Annals of Neurology focuses on the deleterious effects on developing rodent cerebral white matter of a moderate systemic inflammatory insult, 18 apparently less severe than the inflammatory paradigms employed in previous studies. Favrais and colleagues18 simulated a moderate systemic inflammatory state in developing mice from postnatal day 1 (P1) to P5 by daily injections of interleukin (IL)-1b and later evaluated oligodendroglial (OL) development, myelination, behavior, and magnetic resonance imaging (MRI) appearance. The systemic inflammatory state produced was likely complex, because blood levels of tumor necrosis factor (TNF)-a were more prominently increased at P5 than those for IL-1b. The principal findings after 2 to 4 weeks suggested a long-lasting defect in OL maturation, with reduced density of myelinating OLs, increased density of OL progenitors, and disruption of the expression of several transcription factors important in OL maturation. A disturbance of axonal development was also suggested. Reduced white matter anisotropy and memory deficits accompanied the white matter abnormalities. Systemic effects were considered mild. The effectors activated in the brain by the systemic elevations in IL-1b (and TNF-a) were not delineated, although a ‘‘transient’’increase in microglia was noted. The potential mechanisms by which systemic inflammatory compounds, including IL-1b and TNF-a, produce brain effects have been discussed elsewhere, and microglia and microglia-derived factors, for example, reactive oxygen and nitrogen species, often appear to be important. 8, 9, 17, 19–27 Favrais and colleagues18 conclude that ‘‘moderate perinatal systemic inflammation’’produces a ‘‘long-lasting myelination deficit’’that has ‘‘clinical relevance.’’Critics might dispute clinical relevance because of the rather long developmental time period of cytokine administration (P1 to P5 in the mouse), the modest, albeit statistically significant differences in many of the parameters, and the possibilities of species differences in immune responses and in aspects of cellular development in mouse versus human brain. Nevertheless, the findings are interesting and worthy of discussion in the context of current concepts of the encephalopathy of prematurity, particularly the issue of the mechanism (s) underlying the failure of OL maturation in this disorder and the full spectrum of the human pathology. The encephalopathy of prematurity consists of the combination of cerebral white matter injury, that is, periventricular leukomalacia (PVL) in its various forms, and neuronal/axonal deficits. 1, 28 PVL consists of focal necroses deep in cerebral white matter and a more diffuse white matter disturbance. The focal necroses are usually microscopic and followed by glial scars (cysts follow macroscopic necroses, which are now unusual). The more diffuse white …