PARP inhibitors (PARPis) selectively kill BRCA1/2-deficient cancer cells by inducing synthetic lethality, making them a key strategy in targeted cancer therapy. However, many patients with BRCA1/2 mutations do not respond to PARPis, and resistance develops over time. Recent studies have shown that changes in the functional defects of BRCA1/2-deficient cells, particularly their ability to suppress and protect single-stranded DNA gaps, influence the gain or loss of PARPi-induced synthetic lethality. These findings have led to revised models explaining how PARPis selectively kill BRCA-deficient cells and have provided new insights into the mechanisms of PARPi sensitivity and resistance. BRCA1 and BRCA2 are tumor suppressor genes frequently mutated in various cancers. Their loss leads to defects in homologous recombination (HR), increasing DNA damage and genomic instability. BRCA1/2 also play roles in protecting stalled replication forks and preventing DNA gap accumulation. Defects in these functions contribute to genomic instability in cancer cells. The concept of "BRCAness" refers to the functional defects in cancer cells and their consequent vulnerabilities, which can be assessed by measuring HRD levels. PARP inhibitors, such as olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, and AZD5305, are being tested in clinical trials. These drugs inhibit PARP1 and PARP2, with varying potency and selectivity. Olaparib has been approved for various cancers, including ovarian, breast, and pancreatic cancers. Recent studies have shown that PARP inhibition can induce DNA damage by trapping PARP1/2 on DNA, leading to replication catastrophe and cell death in BRCA-deficient cells. Several models have been proposed to explain the mechanisms of PARPi-induced synthetic lethality. These include the accumulation of single-stranded DNA (ssDNA) gaps, the trapping of PARP1/2 on DNA, and the degradation of reversed replication forks in BRCA-deficient cells. These models suggest that the defects in BRCA-deficient cells in protecting ssDNA gaps and replication forks contribute to PARPi sensitivity. Mechanisms of PARPi resistance include the restoration of HR activity, the restoration of fork and gap protection, and the loss of PARP2 activity. These mechanisms can lead to resistance by allowing cancer cells to repair DNA damage or by restoring normal cellular functions. Combination therapies with other DNA damage response (DDR) drugs, such as ATR/Chk1 inhibitors, WEE1/PKMYT1 inhibitors, and inhibitors of gap repair, have shown promise in overcoming PARPi resistance. These combinations target different aspects of DNA repair and can enhance the efficacy of PARPis. Beyond BRCA1/2-mutated cancers, PARPis may also be effective in cancers with other oncPARP inhibitors (PARPis) selectively kill BRCA1/2-deficient cancer cells by inducing synthetic lethality, making them a key strategy in targeted cancer therapy. However, many patients with BRCA1/2 mutations do not respond to PARPis, and resistance develops over time. Recent studies have shown that changes in the functional defects of BRCA1/2-deficient cells, particularly their ability to suppress and protect single-stranded DNA gaps, influence the gain or loss of PARPi-induced synthetic lethality. These findings have led to revised models explaining how PARPis selectively kill BRCA-deficient cells and have provided new insights into the mechanisms of PARPi sensitivity and resistance. BRCA1 and BRCA2 are tumor suppressor genes frequently mutated in various cancers. Their loss leads to defects in homologous recombination (HR), increasing DNA damage and genomic instability. BRCA1/2 also play roles in protecting stalled replication forks and preventing DNA gap accumulation. Defects in these functions contribute to genomic instability in cancer cells. The concept of "BRCAness" refers to the functional defects in cancer cells and their consequent vulnerabilities, which can be assessed by measuring HRD levels. PARP inhibitors, such as olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, and AZD5305, are being tested in clinical trials. These drugs inhibit PARP1 and PARP2, with varying potency and selectivity. Olaparib has been approved for various cancers, including ovarian, breast, and pancreatic cancers. Recent studies have shown that PARP inhibition can induce DNA damage by trapping PARP1/2 on DNA, leading to replication catastrophe and cell death in BRCA-deficient cells. Several models have been proposed to explain the mechanisms of PARPi-induced synthetic lethality. These include the accumulation of single-stranded DNA (ssDNA) gaps, the trapping of PARP1/2 on DNA, and the degradation of reversed replication forks in BRCA-deficient cells. These models suggest that the defects in BRCA-deficient cells in protecting ssDNA gaps and replication forks contribute to PARPi sensitivity. Mechanisms of PARPi resistance include the restoration of HR activity, the restoration of fork and gap protection, and the loss of PARP2 activity. These mechanisms can lead to resistance by allowing cancer cells to repair DNA damage or by restoring normal cellular functions. Combination therapies with other DNA damage response (DDR) drugs, such as ATR/Chk1 inhibitors, WEE1/PKMYT1 inhibitors, and inhibitors of gap repair, have shown promise in overcoming PARPi resistance. These combinations target different aspects of DNA repair and can enhance the efficacy of PARPis. Beyond BRCA1/2-mutated cancers, PARPis may also be effective in cancers with other onc