PARP inhibitors (PARPi) are the first clinically approved drugs that exploit synthetic lethality, a genetic concept that describes the situation where a defect in one gene leads to cell death when combined with a defect in another gene. PARPi target PARP1 and PARP2, enzymes involved in DNA repair, and are effective in tumors with BRCA1 or BRCA2 mutations, which have impaired DNA repair. PARPi also show promise in other cancers with similar repair defects. However, resistance to PARPi develops in advanced cancers, and the optimal use in combination therapies remains challenging. PARPi work by trapping PARP1 on DNA, preventing its autoPARylation and interfering with DNA repair. This mechanism is more effective in some PARPi than others, influencing their cytotoxic potency. Clinical trials have shown that PARPi, such as olaparib, rucaparib, and niraparib, are effective in BRCA-mutated cancers, including ovarian, breast, and prostate cancers. These drugs have been approved for use in patients with advanced cancers who have germline or somatic BRCA mutations. PARPi also show potential in tumors with "BRCAness," a phenotype similar to BRCA mutations, which includes tumors with homologous recombination repair defects. PARPi may also be effective in tumors with other DNA repair defects, such as those involving ATM, ATR, or PALB2. PARPi are being tested in combination with other therapies, including chemotherapy, immunotherapy, and targeted agents. These combinations aim to enhance the anti-tumor effect by creating DNA damage or modulating DNA repair. However, the optimal combination and sequencing of PARPi with other drugs remain areas of active research. PARPi may also be beneficial when combined with drugs that target cancer-specific features unrelated to DNA repair or BRCA function. The development of PARPi highlights the potential of synthetic lethality as a strategy for cancer therapy. However, challenges remain in identifying predictive biomarkers for PARPi response and overcoming resistance. Future research will focus on understanding the mechanisms of PARPi action, improving their clinical effectiveness, and developing combination therapies that maximize their therapeutic potential. The successful development of PARPi for BRCA mutant cancers provides proof-of-concept that synthetic lethality can be translated into effective cancer therapies.PARP inhibitors (PARPi) are the first clinically approved drugs that exploit synthetic lethality, a genetic concept that describes the situation where a defect in one gene leads to cell death when combined with a defect in another gene. PARPi target PARP1 and PARP2, enzymes involved in DNA repair, and are effective in tumors with BRCA1 or BRCA2 mutations, which have impaired DNA repair. PARPi also show promise in other cancers with similar repair defects. However, resistance to PARPi develops in advanced cancers, and the optimal use in combination therapies remains challenging. PARPi work by trapping PARP1 on DNA, preventing its autoPARylation and interfering with DNA repair. This mechanism is more effective in some PARPi than others, influencing their cytotoxic potency. Clinical trials have shown that PARPi, such as olaparib, rucaparib, and niraparib, are effective in BRCA-mutated cancers, including ovarian, breast, and prostate cancers. These drugs have been approved for use in patients with advanced cancers who have germline or somatic BRCA mutations. PARPi also show potential in tumors with "BRCAness," a phenotype similar to BRCA mutations, which includes tumors with homologous recombination repair defects. PARPi may also be effective in tumors with other DNA repair defects, such as those involving ATM, ATR, or PALB2. PARPi are being tested in combination with other therapies, including chemotherapy, immunotherapy, and targeted agents. These combinations aim to enhance the anti-tumor effect by creating DNA damage or modulating DNA repair. However, the optimal combination and sequencing of PARPi with other drugs remain areas of active research. PARPi may also be beneficial when combined with drugs that target cancer-specific features unrelated to DNA repair or BRCA function. The development of PARPi highlights the potential of synthetic lethality as a strategy for cancer therapy. However, challenges remain in identifying predictive biomarkers for PARPi response and overcoming resistance. Future research will focus on understanding the mechanisms of PARPi action, improving their clinical effectiveness, and developing combination therapies that maximize their therapeutic potential. The successful development of PARPi for BRCA mutant cancers provides proof-of-concept that synthetic lethality can be translated into effective cancer therapies.