The calcium-permeable TRPM2 ion channel is expressed in neurons in the cortex, hippocampus, striatum, and brainstem, among other regions and is activated following oxidative stress, induced by exogenous hydrogen peroxide. TRPM2 channels were initially identified and extensively characterized by our group, and subsequently branded as a novel “death channel” in neurons, because of their contribution to unregulated influx of Ca2+ following oxidative stress. Indeed, the most well-characterized role for TRPM2 is as an executioner of cell death following oxidative stress, leading to excessive Ca2+ influx and consequent cell death. We recently demonstrated that inhibition/genetic knockdown of TRPM2 protects neurons in a gender-specific manner and provides a promising target for neuroprotection in males. In vivo, in vitro, electrophysiology and biochemical tools are being used to identify novel inhibitors of TRPM2 and elucidate the pathways leading to sex-specific activation of this channel following either stroke or cardiac arrest.