Abstract: Ischemic stroke represents a heavy burden on public health. Currently, recanalization is the only effective therapy for ischemic stroke in a small population of eligible patients. However, there is no effective adjunct medication for preventing neuron loss after reperfusion to mitigate long-lasting brain injury. Extrasynaptic N-methyl-D-aspartate receptors (esNMDARs) are the major cause of ischemic neuronal death. However, there is no inhibitor selectively targeting esNMDARs without compromising the function of other “beneficial” synaptic NMDARs, which is due to the limited understanding of the underlying molecular mechanisms. Recently, two members of the transient receptor potential melastatin (TRPM) channel family, TRPM2 and TRPM4, were shown to be critical in amplifying esNMDAR-mediated neurotoxic effects during ischemic stroke without influencing the functions of synaptic NMDAR. Targeting the interaction between TRPM2- and TRPM4-esNMDAR provides a novel strategy in screening effective drugs for ischemic stroke.