Cystic periventricular leukomalacia (PVL) is one of the most severe and frequent cause of cerebral palsy in children surviving preterm birth. The pathogenesis of PVL yet is not completely understood. The majority of the theories consider the necrotic foci to be hypoxic-ischemic lesions, resulting from impaired perfusion at the vascular border zones between ventriculopedal and ventriculofugal arteries, as the latter are poorly developed in preterm infants. Besides periventricular vascular anatomic factors and pressure-passive cerebral circulation the intrinsic vulnerability of cerebral white matter (a particular vulnerability of rapidly differentiating oligodendroglial cells) of preterm infants plays an important role. An alternative view focuses on the role of intrauterine infection and the fetal inflammatory response syndrome. Hypocarbia has been identified as an independent risk factor for PVL in many studies. As far as the pathogenesis of PVL is complex and likely multifactorial, the influence of hypocarbia on subsequent white matter damage is most striking in postnatal acquired and late onset cystic PVL. This review analyses clinical trials demonstrating an association between hypocarbia and PVL. Physiological studies on cerebrovascular autoregulation and animal studies presented in this review try to elucidate the underlying mechanisms.