Neuronal cell death is a major feature of various diseases, including brain ischemia, neuronal degenerative diseases, and traumatic injury, suggesting the importance of investigating the mechanisms that mediate neuronal cell death. Although the various factors that contribute to brain ischemia have been defined and the mechanism through which each factor causes neuronal cell death has been investigated, definite strategies have not been established. In this brief review, we focus on two important mechanisms that contribute to the pathogenesis of brain ischemia. First, we discuss the glutamate theory, a proposed mechanism for the understanding of ischemia-induced neuronal cell death. Second, an accumulation of recent molecular neurobiology evidence regarding the dysfunction of a cellular organelle, the endoplasmic reticulum (ER), suggests that it plays a major role in the pathogenesis of neuronal cell death. Whereas the former theory reflects the role of neuron-specific factors in the induction of cell death, the stress response of the ER for maintenance of its function is regarded as a defense mechanism. Because hypoxia, another major factor in ischemia, results in further dysfunction of the ER, studies on the malfunction of this cellular organelle may facilitate the development of novel strategies to block ischemia-induced cell death.