Poly(ADP-ribose) polymerases (PARPs) play a crucial role in regulating various cellular functions, particularly DNA repair, energy metabolism, and inflammation. PARP1, the primary isoform of PARPs, is involved in DNA repair by facilitating the recruitment of repair enzymes and promoting chromatin relaxation. It also depletes cellular NAD+ pools, leading to energy dysfunction and cell necrosis. Additionally, PARP1 promotes the transcription of pro-inflammatory genes, contributing to inflammation. Pharmacological inhibitors of PARP have shown potential in enhancing the cytotoxicity of anticancer drugs, reducing cell necrosis in conditions like stroke and myocardial infarction, and downregulating multiple inflammatory pathways. The first ultra-potent PARP inhibitors have entered clinical trials. This review discusses the pathophysiological pathways and mechanisms governed by PARP, as well as the therapeutic actions of various classes of novel PARP inhibitors.Poly(ADP-ribose) polymerases (PARPs) play a crucial role in regulating various cellular functions, particularly DNA repair, energy metabolism, and inflammation. PARP1, the primary isoform of PARPs, is involved in DNA repair by facilitating the recruitment of repair enzymes and promoting chromatin relaxation. It also depletes cellular NAD+ pools, leading to energy dysfunction and cell necrosis. Additionally, PARP1 promotes the transcription of pro-inflammatory genes, contributing to inflammation. Pharmacological inhibitors of PARP have shown potential in enhancing the cytotoxicity of anticancer drugs, reducing cell necrosis in conditions like stroke and myocardial infarction, and downregulating multiple inflammatory pathways. The first ultra-potent PARP inhibitors have entered clinical trials. This review discusses the pathophysiological pathways and mechanisms governed by PARP, as well as the therapeutic actions of various classes of novel PARP inhibitors.