Over the past decade, poly(ADP-ribosyl)ation has emerged as a crucial event in the pathogenesis of ischemic stroke. A large body of evidence unambiguously demonstrates that activity of poly(ADP-ribose) polymerase-1 (PARP-1) significantly increases during brain ischemia, and that inhibition of this enzymatic activity affords substantial neuroprotection from ischemic brain injury. This review strictly focuses on literature on poly(ADP-ribosyl)ation and ischemic stroke, highlighting the pathogenetic role of poly(ADP-ribose) in ischemic neuronal death, and the therapeutic relevance of drugs modulating its metabolism to pharmacological treatment of cerebral ischemia.