The N-methyl D-aspartate receptor (NMDAR) is an excitatory ligand-gated ion channel that is integral for neurological function because of its roles in synaptic plasticity and in cell survival. Until a decade ago, the NMDAR was also thought to be the key mediator of excitotoxicity during ischemia; a notion that was challenged when clinical trials of NMDAR blockers for the treatment of ischemic stroke were deemed either ineffective or the drugs not clinically tolerated. New evidence has emerged suggesting that Pannexin ion channels are modulated by NMDARs and may be critical in perpetuating ischemic cell death. This provides a novel avenue for stroke research and intervention, and may reconcile the lack of clinical efficacy for NMDAR antagonism. This thesis explores the contributions of pannexin-1 (Panx1) and NMDA receptors in models of ischemia/hypoxia and aims to understand their role in ischemic excitotoxicity. My over-arching hypothesis is that co-activation of NMDA receptors and Panx1 is important for pathological and physiological signaling. Here I show that NMDARs are key activators of Panx1, which occurs through an unexpected mechanism that does not rely on ion movement through the NMDAR pore. This non-canonical mechanism of NMDAR signaling is critical for neuronal death during O2 / glucose deprivation (OGD) and during overstimulation of NMDA receptors. Critical elements of non-canonical NMDAR function were identified, including Src family kinases and Panx1, which exist in a signaling complex. Finally, I show that non-canonical activation of NMDARs can recruit Panx1 channels and induce long-term depression of excitatory synapses in the hippocampus. In conclusion, the work of this thesis has identified a novel transduction pathway that has broad reaching implications for our understanding of ischemia and synaptic physiology.