- Spreading depolarization (SD) is a phenomenon of various cerebral gray matter structures that only occurs under pathological conditions. In the present paper, we summarize the evidence from several decades of research that SD and cytotoxic edema in these structures are largely overlapping terms. SD/cytotoxic edema is a toxic state that - albeit initially reversible - leads eventually to cellular death when it is persistent. Both hemorrhagic and ischemic stroke are among the most prominent causes of SD/cytotoxic edema. SD/cytotoxic edema is the principal mechanism that mediates neuronal death in these conditions. This applies to gray matter structures in both the ischemic core and the penumbra. SD/cytotoxic edema is often a single terminal event in the core whereas, in the penumbra, a cluster of repetitive prolonged SDs is typical. SD/cytotoxic edema also propagates widely into healthy surrounding tissue as short-lasting, relatively harmless events so that regional electrocorticographic monitoring affords even remote detection of ischemic zones. Ischemia cannot only cause SD/cytotoxic edema but it can also be its consequence through inverse neurovascular coupling. Under this condition, ischemia does not start simultaneously in different regions but spreads in the tissue driven by SD/cytotoxic edema-induced microvascular constriction (= spreading ischemia). Spreading ischemia prolongs SD/cytotoxic edema. Thus, it increases the likelihood for the transition from SD/cytotoxic edema into cellular death. Vasogenic edema is the other major type of cerebral edema with relevance to ischemic stroke. It results from opening of the blood-brain barrier. SD/cytotoxic edema and vasogenic edema are distinct processes with important mutual interactions.