Excitotoxic stress is potentially an important component of disorders such as stroke and neurodegenerative diseases. Its toxic effects appear to be transduced through mechanisms that result in both acute and delayed forms of death. We examined here whether cyclin dependent kinases (CDKs), molecules normally associated with cell cycle control, may be involved in delayed excitotoxic death in two different excitotoxin models. We show that nuclear localized cyclin D1, an activator of Cdk4/6, is upregulated during kainic acid evoked death of CA3/CA1 neurons and that this upregulation is associated with increased phosphorylation of a critical CDK substrate, pRb. In addition, we find that the CDK inhibitor, flavopiridol blocks the delayed death of cultured cortical neurons evoked by 3-nitroproprionic acid, an inhibitor of the mitochondrial electron transport chain, treatment and that the NMDA antagonist, MK801 provides short term protection in this model. Full, long-term protection occurs when both flavopiridol and MK-801 are present. Taken together, these data support a role for cell cycle regulators in neuronal death evoked by excitotoxic stress and indicate a potential therapeutic target for treatment of excitotoxicity-related disorders.