Synthetic lethality (SL) has emerged as a promising strategy in anticancer therapy, particularly for targeting challenging tumor suppressor genes. The concept of SL is based on the idea that the simultaneous disruption of two genes, which are individually viable, leads to cell death. This approach has been successfully applied in the treatment of BRCA1/2-defective tumors using PARP inhibitors (PARPi), which exploit the DNA damage response (DDR) pathway. PARPi work by trapping the PARP enzyme on chromatin, leading to the conversion of single-stranded DNA breaks (SSBs) into double-stranded breaks (DSBs), which are repaired through homologous recombination (HR). In BRCA1/2-deficient cells, this process is impaired, leading to cell death via SL. Recent advancements in SL research have expanded beyond the DDR pathway, with new targets such as PARG, USP1, Polθ, RAD51, and RAD52 being explored. These targets offer new opportunities for developing SL-based therapies. For example, PARG inhibitors (PARGi) have shown potential in BRCA2-deficient tumors, while USP1 inhibitors have demonstrated efficacy in BRCA1/2 mutant tumors. Polθ inhibitors have also shown promise in HR-deficient cancers, and RAD51 inhibitors have been investigated as a strategy to induce SL with PARPi. The development of selective inhibitors for these targets has been a focus of recent research, with compounds such as NMS-P118, AZD5305, and IDE161 showing promising preclinical results. Additionally, the combination of PARPi with other therapies, such as immunotherapy and epigenetic modulators, has shown potential in enhancing efficacy and overcoming resistance. The future of SL-based therapies lies in the continued exploration of new targets and the development of more selective and potent inhibitors, which could lead to more effective and personalized cancer treatments.Synthetic lethality (SL) has emerged as a promising strategy in anticancer therapy, particularly for targeting challenging tumor suppressor genes. The concept of SL is based on the idea that the simultaneous disruption of two genes, which are individually viable, leads to cell death. This approach has been successfully applied in the treatment of BRCA1/2-defective tumors using PARP inhibitors (PARPi), which exploit the DNA damage response (DDR) pathway. PARPi work by trapping the PARP enzyme on chromatin, leading to the conversion of single-stranded DNA breaks (SSBs) into double-stranded breaks (DSBs), which are repaired through homologous recombination (HR). In BRCA1/2-deficient cells, this process is impaired, leading to cell death via SL. Recent advancements in SL research have expanded beyond the DDR pathway, with new targets such as PARG, USP1, Polθ, RAD51, and RAD52 being explored. These targets offer new opportunities for developing SL-based therapies. For example, PARG inhibitors (PARGi) have shown potential in BRCA2-deficient tumors, while USP1 inhibitors have demonstrated efficacy in BRCA1/2 mutant tumors. Polθ inhibitors have also shown promise in HR-deficient cancers, and RAD51 inhibitors have been investigated as a strategy to induce SL with PARPi. The development of selective inhibitors for these targets has been a focus of recent research, with compounds such as NMS-P118, AZD5305, and IDE161 showing promising preclinical results. Additionally, the combination of PARPi with other therapies, such as immunotherapy and epigenetic modulators, has shown potential in enhancing efficacy and overcoming resistance. The future of SL-based therapies lies in the continued exploration of new targets and the development of more selective and potent inhibitors, which could lead to more effective and personalized cancer treatments.