Poly(ADP-ribose) polymerase-1 (PARP-1) plays a primary role in the process of poly(ADP-ribosyl)ation. This posttranslational modification of nuclear proteins is activated in response to DNA damage. Having been studied for more than 30 years, PARP-1 is now known to be implicated in several crucial cellular processes: DNA replication, transcription, DNA repair, apoptosis, and genome stability. In this review, we focus on recent findings suggesting that PARP-1 participates in DNA damage signaling in cell death. Of clinical relevance is its role in cancer therapy, irradiation, and chemotherapy, all of which may cause DNA damage and overactivate PARP-1, resulting in inflammation caused by necrosis. Therefore, we will discuss how inhibition of PARP-1 may enhance the efficiency of cancer therapy.