We have developed a novel way to block TRPM4 channel by applying specific antibodies that bind to an extracellular region close to the channel pore. The TRPM4 antibodies include a polyclonal antibody M4P that is specific to rodent TRPM4, a monoclonal antibody M4M that is specific to human TRPM4, and most recently, a humanized antibody M4H modified from M4M.The inhibitory effect of TRPM4 antibodies is achieved via two pathways: 1) directly blocking channel activity; 2) downregulating the surface expression of TRPM4. Under disease condition such as hypoxia/ischemia, blocking TRPM4 activity by our antibodies attenuates oncotic cell death in vascular endothelial cells and neurons. Excitingly, TRPM4 blocking antibody was revealed to repolarize membrane potential of hypoxic neurons, and inhibit calcium influx via NMDA receptors which is critical for excitotoxicity. Importantly, TRPM4 blocking antibodies have no effect on healthy cells as the expression of TRPM4 is low in these cells, and the channel remains inactivated.TRPM4 blocking antibodies demonstrate great therapeutic potential in neurological diseases. In stroke, TRPM4 antibodies could attenuate reperfusion injury during both early and delayed recanalization. It has the potential to extend the current time window of reperfusion therapy. In animal model of vascular dementia, TRPM4 antibodies were found to improve learning and memory by protecting hippocampal neurons from chronic hypoxia. In traumatic head injury, TRPM4 antibodies could improve functional recovery. With the potent effect on vascular protection and neuroprotection, TRPM4 antibody can benefit the management of neurological diseases with hypoxia/ischemia.