During ischemic stroke, the reduced oxygen supply to affected of regions of the brain induces a switch in glucose utilisation from oxidative phosphorylation to glycolysis, which leads to lactic acidosis. The resultant drop in pH activates acid-sensing ion channel 1a (ASIC1a), a proton-gated sodium channel. Most mammals express six ASIC subtypes, but ASIC1a is the dominant subtype in human and rodent brain. Activation of ASIC1a appears to promote neuronal death both by exacerbating intracellular calcium overload and directly activating the necroptosis programmed cell death pathway. We recently isolated a disulfide-rich spider-venom peptide (Hi1a) from the deadly Australian funnel-web spider that inhibits ASIC1a with 20,000-fold higher potency than amiloride. We demonstrated that Hi1a dramatically reduces infarct size and improves behavioural outcomes even when administered up to 8 hours after an ischemic stroke in rats (PNAS 114:3750–3755, 2017). Analogous to the situation in the brain, myocardial extracellular pH can fall rapidly during sustained cardiac ischemia such as occurs during myocardial infarction. We have found that ASIC1a is the dominant subtype in human and rodent cardiomyocytes, and that human induced pluripotent stem cell-derived cardiomyocytes can be rescued from hypoxic injury by treatment with Hi1a. Moreover, in an ex vivo model of cardiac ischemia-reperfusion injury, genetic ablation of ASIC1a or treatment with Hi1a greatly improved cardiac recovery. Finally, we have found that Hi1a preserves the integrity of donor hearts destined for transplant, regardless of whether the hearts were obtained by the brain death or circulatory death pathway. In summary, venom peptide Hi1a appears to be a promising lead molecule for treating ischemic injuries of the heart and brain.