APC (activated protein C), derived from the plasma protease zymogen, is antithrombotic and anti-inflammatory. In preclinical injury models, recombinant APC provides neuroprotection for multiple injuries, including ischemic stroke. APC acts directly on brain endothelial cells and neurons by initiating cell signaling that requires multiple receptors. Two or more major APC receptors mediate APC’s neuroprotective cell signaling. When bound to endothelial cell protein C receptor, APC can cleave protease-activated receptor 1, causing biased cytoprotective signaling that reduces ischemia-induced injury. Pharmacological APC alleviates bleeding induced by tissue-type plasminogen activator in murine ischemic stroke studies. Remarkably, APC’s signaling promotes neurogenesis. The signaling-selective recombinant variant of APC, 3K3A-APC, was engineered to lack most of the APC’s anticoagulant activity but retain APC’s cell signaling actions. Recombinant 3K3A-APC is in ongoing National Institutes of Health (NIH)–funded clinical trials for ischemic stroke.