During status epilepticus (SE), a host of physiologic changes occur in the brain, other organs, and the circulation, many of which influence the risk of central nervous system (CNS) injury. Early observations on brain injury in epilepsy and theories of its pathogenesis were reviewed in a previous volume on SE, in which the theory that intracellular calcium toxicity is the ultimate factor responsible was also presented (44). This chapter summarizes the systemic physiologic changes and alterations in cardiopulmonary function during SE and their implications for cell death. The concepts of (1) a dissociation between electroencephalographic (EEG) seizure duration and neural injury and (2) epileptic tolerance will be presented.