Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme which is catalytically activated by DNA strand interruptions. The involvement of PARP has been implicated in different cellular responses to genotoxic damage, including cell survival, DNA repair, transformation, and cell death. However, the exact contribution of PARP polypeptide or its enzymatic product has remained ill defined. Recent studies with two different PARP knock out mice have demonstrated the beneficial role of PARP in maintaining genomic integrity and in survival responses after exposure to whole body gamma-irradiation. Other studies have demonstrated the instrumental role of PARP in death of the neuronal cells after ischemia-reperfusion injury. The recombination inhibiting function of PARP at DNA strand breaks was more evident in a model system deficient in activities of two major DNA strand break binding proteins, PARP and DNA-dependent protein kinase. The present review summarizes similarities and differences obtained with the two PARP knock out mice and reanalyzes the role of PARP in various cellular responses to DNA damage.