Various surgical procedures require that the normal cerebral blood flow to the brain be interrupted. This challenges surgeons to find means of protecting the brain during these extremely vulnerable periods. Accumulative evidence has shown that the mechanisms underlying neuronal injury is multifactorial, something, which has been attributed to the exceptional complexity of the brain in both, structure and function. As such, efforts to define the best strategies for neuroprotection during circulatory arrest are formidable, at best. Hypothermia has become a cornerstone for cerebral protection during cardiopulmonary bypass (CPB) and is applied to offset the deleterious effects of oxygen deprivation on the brain. The evidence suggests that hypothermia has some action in inhibiting most of injury-inducing processes. Recently, emerging data has indicated that the mechanisms and outcomes of ischemic injury are strongly influenced by biological sex, as well as sex hormones. These observations have further confounded neuroprotection efforts. Despite the various neuroprotective strategies that have recently been introduced, mild hypothermic-circulatory arrest is still commonly used in cardiovascular surgeries. The aim here is to examine the current understanding of the underlying mechanisms of ischemia-induced cerebral injury, to outline the neuroprotective actions of HCA, and finally, briefly outline evidence supporting gender differences in cerebral injury.