The process of protein modification by adding or detaching small ubiquitin-like modifiers (SUMO) proteins, called SUMOylation, contributes to the regulation of numerous processes in eukaryotic cells. SUMOylation also represents a key response and adaption mechanism to different forms of metabolic stress. The central nervous system (CNS) and neurons in particular are highly susceptible to hypoxic-ischemic stress due to the lack of significant oxygen and energy reserves. SUMOylation is observed in many molecular responses to metabolic stress in the brain, and is therefore supposed to represent an endogenous neuroprotective mechanism. However, the detailed roles of SUMOylation during CNS hypoxia-ischemia are not well understood so far. Moreover, SUMOylation is subjected to complex regulatory mechanisms and might exert protective, but also detrimental processes during hypoxic-ischemic stress. This review provides a comprehensive overview on SUMOylation processes under physiological and pathological conditions in the CNS. A particular spotlight is set on clinically relevant hypoxic-ischemic conditions such as stroke by focusing on peri- and postischemic SUMOylation in neurons and astrocytes. The review describes relevant SUMOylation targets in these cells to discuss confirmed and supposed downstream mechanisms potentially contributing to neuroprotection, but also to sometimes detrimental processes. The review further provides unique insights into the time course of SUMO responses during cerebral ischemia in different cerebral cell populations. This includes neurons, astrocytes, but also phagocytes that become activated (microglia) and/or migrate (macrophages/monocytes) to the ischemic CNS. Based on this compact knowledge, the review finally suggests potential directions for future basic and translational research.