Silent information regulator 1 (SIRT1) is a NAD+-dependent histone deacetylase that represses gene expression and plays a role in longevity. SIRT1 responds to diverse stress conditions and regulates metabolism in nutrient deficiency conditions; therefore, it is involved in adaptive pathways to better fulfill tissue needs in a disturbed environment. SIRT1 overexpression or activation is protective in neurodegenerative diseases. Its role in acute nervous system injury, such as brain ischemia, is emerging, but whether SIRT1 activation improves stroke outcome is still a matter of controversy. In the present review, we will document present knowledge about the contribution of SIRT1 in death/survival in cell and animal models of brain ischemia and discuss whether SIRT1 could be a valuable target for therapeutic intervention in human stroke.