The article "New Horizons of Synthetic Lethality in Cancer: Current Development and Future Perspectives" by Viola Previtali et al. reviews the recent advancements in synthetic lethality (SL) as a paradigm for anticancer therapies. SL, initially observed in fruit flies and yeast, involves the combined alteration of individually viable genes, leading to the selective targeting of cancer cells with mutated or inactivated driver genes. The authors highlight the expansion of SL targets beyond poly(ADP-ribose) polymerase (PARP) inhibitors used for BRCA1/2-defective tumors, focusing on molecular targets within the DNA damage response (DDR) that have rapidly entered clinical trials. The article discusses the design and therapeutic strategies of SL targets and inhibitors, emphasizing classical SL in drug discovery, including the identification of novel drug targets, development of synergistic drug combinations, and stratification of cancer patients for tailored therapies. A significant portion of the review is dedicated to DDR targets, particularly PARP and BRCA1/2, and their inhibitors. The success of PARP inhibitors (PARPi) in treating BRCA1/2-deficient tumors is highlighted, along with the challenges of toxicity and resistance, and the exploration of combination therapies to enhance efficacy. The authors also explore new SL targets outside the DDR, such as PARG, USP1, Polθ, RAD51, RAD52, and nuclear kinases like ATR, ATM, and DNA-PK. These targets offer promising directions for future drug discovery, particularly in overcoming resistance and reducing side effects. The article concludes by discussing current challenges and new opportunities in the field of SL research, aiming to stimulate discussion and further investigation in medicinal chemistry.The article "New Horizons of Synthetic Lethality in Cancer: Current Development and Future Perspectives" by Viola Previtali et al. reviews the recent advancements in synthetic lethality (SL) as a paradigm for anticancer therapies. SL, initially observed in fruit flies and yeast, involves the combined alteration of individually viable genes, leading to the selective targeting of cancer cells with mutated or inactivated driver genes. The authors highlight the expansion of SL targets beyond poly(ADP-ribose) polymerase (PARP) inhibitors used for BRCA1/2-defective tumors, focusing on molecular targets within the DNA damage response (DDR) that have rapidly entered clinical trials. The article discusses the design and therapeutic strategies of SL targets and inhibitors, emphasizing classical SL in drug discovery, including the identification of novel drug targets, development of synergistic drug combinations, and stratification of cancer patients for tailored therapies. A significant portion of the review is dedicated to DDR targets, particularly PARP and BRCA1/2, and their inhibitors. The success of PARP inhibitors (PARPi) in treating BRCA1/2-deficient tumors is highlighted, along with the challenges of toxicity and resistance, and the exploration of combination therapies to enhance efficacy. The authors also explore new SL targets outside the DDR, such as PARG, USP1, Polθ, RAD51, RAD52, and nuclear kinases like ATR, ATM, and DNA-PK. These targets offer promising directions for future drug discovery, particularly in overcoming resistance and reducing side effects. The article concludes by discussing current challenges and new opportunities in the field of SL research, aiming to stimulate discussion and further investigation in medicinal chemistry.