The article reviews the recent advancements in understanding the structure and function of poly(ADP-ribose) polymerases (PARPs) and their potential as chemotherapeutic targets. PARP1, a key enzyme in DNA repair, is activated by DNA strand breaks and plays a crucial role in maintaining genomic integrity. The hyperactivation of PARP1 leads to the depletion of NAD+ and ATP, potentially causing cell death through parthanatos, a form of metabolic cell death. PARP inhibitors, which target PARP1, have shown promise in treating cancers with defects in DNA repair, such as BRCA1/2-mutant tumors. These inhibitors enhance the cytotoxic effects of DNA-damaging agents, leading to synthetic lethality in these tumor types. However, the long-term effects of PARP inhibitors, particularly on cardiovascular and mental health, need further investigation. The article also discusses the roles of other PARP family members and the challenges in developing more selective and potent PARP inhibitors. Despite the progress, several fundamental questions remain unanswered, including the detailed mechanisms of PARP activation and the broader roles of PARPs in cellular processes.The article reviews the recent advancements in understanding the structure and function of poly(ADP-ribose) polymerases (PARPs) and their potential as chemotherapeutic targets. PARP1, a key enzyme in DNA repair, is activated by DNA strand breaks and plays a crucial role in maintaining genomic integrity. The hyperactivation of PARP1 leads to the depletion of NAD+ and ATP, potentially causing cell death through parthanatos, a form of metabolic cell death. PARP inhibitors, which target PARP1, have shown promise in treating cancers with defects in DNA repair, such as BRCA1/2-mutant tumors. These inhibitors enhance the cytotoxic effects of DNA-damaging agents, leading to synthetic lethality in these tumor types. However, the long-term effects of PARP inhibitors, particularly on cardiovascular and mental health, need further investigation. The article also discusses the roles of other PARP family members and the challenges in developing more selective and potent PARP inhibitors. Despite the progress, several fundamental questions remain unanswered, including the detailed mechanisms of PARP activation and the broader roles of PARPs in cellular processes.