Programmed cell death, often in the form of apoptosis, is an important contributing mechanism in the pathogenesis of ischemic brain injury. Depending on the severity of the insult and the stage of the injury, the executional pathways that are directly responsible for cell death and the signaling mechanisms that participate in the regulation of these death pathways may vary. It is likely that molecular or pharmacological targeting of the upstream signaling mechanisms that control the death executional pathways may offer opportunities for more complete and long-term neuroprotection. This review summarizes the recent advancements in the understanding of the executional and regulatory signaling mechanisms in ischemic brain injury.