RSR13 binds to hemoglobin (Hb), reduces oxygen (O2) binding affinity, and enhances O2 unloading from Hb to hypoxic tissue. Tissue hypoxia is common to cancer, surgery, myocardial ischemia, and stroke. RSR13 increases tumor pO2, reduces tumor hypoxic fraction and because O2 is necessary to maximize the effectiveness of radiation therapy, RSR13 enhances the efficacy of radiation therapy. Patients with brain metastases or glioblastoma multiforme receiving RSR13 and radiation therapy have improved median survival, compared to matched historical controls. Myocardial and cerebral hypoxia can be complications to cardiopulmonary bypass (CPB) surgery. RSR13 improves myocardial oxidative metabolism and contractile function in models of myocardial ischemia, including CPB. In CPB patients, RSR13 improved cardiac contractile function and reduced blood product use. In animals, RSR13 increased brain pO2 and reduced neuronal cell death following cerebral ischemia, alone or in combination with excitotoxic neurotransmitter inhibition. Allosteric modification of Hb by RSR13 represents a unique therapeutic strategy.