Vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang1) were originally identified as endothelial-specific ligands regulating key functions of the vasculature important in stroke. There is increasing evidence that these ligands also exert effects on neurons. Here we review the neuronal effects of VEGF and Ang1 and highlight their potential for therapeutic manipulation in stroke. VEGF stimulates angiogenesis whereas Ang1 suppresses leakage, inflammation and regression of microvessels. Expression of both ligands change dramatically in the brain in experimental stroke, correlating with increased vascular leakage and inflammation. In addition to vascular effects, VEGF can stimulate survival, migration and proliferation of neurons suggesting roles in neural protection and possible therapeutic applications, an idea supported by preclinical studies. Recent reports now demonstrate that Ang1 can also act directly on neurons and enhance neural repair. The realization that VEGF and Ang1 have effects on both neural and vascular compartments impacted by stroke provides new opportunities for therapeutic manipulation to promote neuroprotection and extend the thrombolytic window, as well as stimulating neurogenesis and revascularization.