Numerous studies have indicated oxidative stress as a key pathological factor in ischemic brain injury. One of the key links between oxidative stress and cell death is excessive activation of poly(ADP-ribose) polymerase-1 (PARP-1), which plays an important role in the ischemic brain damage in male animals. Multiple studies have also suggested that NAD+ depletion mediates PARP-1 cytotoxicity, and NAD+ administration can decrease ischemic brain injury. A number of recent studies have provided novel information regarding the mechanisms underlying the roles of oxidative stress and NAD+-dependent enzymes in ischemic brain injury. Of particular interest, there have been exciting progresses regarding the mechanisms underlying the roles of NADPH oxidase and PARP-1 in cerebral ischemia. For examples, it has been suggested that androgen signaling and binding of PARP-1 onto estrogen receptors could account for the intriguing findings that PARP-1 plays remarkably differential roles in the ischemic brain damage of male and female animals; and some studies have suggested casein kinase 2, copper-zinc superoxide dismutase, and estrogen signaling can modulate the expression and activity of NADPH oxidase. This review summarizes these important current advances, and proposes future perspectives for the studies on the roles of oxidative stress and NAD+ in cerebral ischemia. It is increasingly likely that future studies on NAD- and NADP-dependent enzymes, such as NADPH oxidase, PARP-1, and sirtuins, would expose novel mechanisms underlying the roles of oxidative stress in cerebral ischemia, and suggest new therapeutic strategies for treating the debilitating disease.