The article discusses the mechanisms and challenges of using PARP inhibitors (PARPi) to target BRCA1/2-deficient cancer cells, which are often resistant to PARPi therapy. It highlights recent studies that reveal how changes in specific functional defects of BRCA1/2-deficient cells, particularly their defects in suppressing and protecting single-stranded DNA gaps, contribute to the gain or loss of PARPi-induced synthetic lethality. The review covers the development and advancement of PARPi, the mechanisms of action, potential side effects, and mechanisms of PARPi resistance. It also explores combination therapies to overcome PARPi resistance, including combinations with ATR/Chk1 inhibitors, WEE1/PKMYT1 inhibitors, and inhibitors of gap repair. The article concludes by discussing the expanding application of PARPi beyond BRCA1/2-mutated cancers and the importance of understanding the quantitative aspects of synthetic lethality to improve PARPi therapy.The article discusses the mechanisms and challenges of using PARP inhibitors (PARPi) to target BRCA1/2-deficient cancer cells, which are often resistant to PARPi therapy. It highlights recent studies that reveal how changes in specific functional defects of BRCA1/2-deficient cells, particularly their defects in suppressing and protecting single-stranded DNA gaps, contribute to the gain or loss of PARPi-induced synthetic lethality. The review covers the development and advancement of PARPi, the mechanisms of action, potential side effects, and mechanisms of PARPi resistance. It also explores combination therapies to overcome PARPi resistance, including combinations with ATR/Chk1 inhibitors, WEE1/PKMYT1 inhibitors, and inhibitors of gap repair. The article concludes by discussing the expanding application of PARPi beyond BRCA1/2-mutated cancers and the importance of understanding the quantitative aspects of synthetic lethality to improve PARPi therapy.