NAD⁺ and NADH have been emerging as the common mediators of energy metabolism, mitochondrial functions, calcium homeostasis, aging and cell death. NAD⁺ and NADH can affect cell death by various mechanisms, such as influencing energy metabolism, mitochondrial permeability transition pores, and apoptosis-inducing factor. Because energy failure, calcium disregulation and cell death are the key components in the tissue damaging cascade initiated by cerebral ischemia, it is likely that NAD⁺ and NADH play significant roles in ischemic brain damage. Many studies, including the findings that poly(ADP-ribose) polymerase-1 mediates ischemic brain injury and that NAD⁺ administration can decrease ischemic brain damage, have suggested significant roles of NAD⁺ and NADH in the debilitating illness. However, there is still distinct insufficiency of the information regarding the roles of NAD⁺ and NADH in ischemic brain injury. Because increasing evidence has indicated critical functions of NAD⁺ and NADH in various biological processes, future studies on the roles of NAD⁺ and NADH in cerebral ischemia may expose essential mechanisms underlying ischemic brain injury and suggest novel therapeutic strategies for the illness.