In recent years, synthetic lethality has been regarded as a sound example of cancer treatment. Identifying a growing number of synthetic lethality targets has led to a substantial broadening of the application of synthetic lethality, well beyond the PAPR inhibitors employed for treating tumors with BRCA1/2 deficiencies. Especially, molecular targets within the DDR have furnished inhibitor sources and have rapidly advanced to clinical trials. In this review, we summarize the DDR-associated synthetic lethality targets such as WRN, USP1, PARP, ATR, DNA-PK, PRMT5, POLQ, and WEE1. These targets allow for the development of targeted modulators like inhibitors and degraders. Additionally, we emphasize the rational design, advantages, and potential limitations. Furthermore, we outline the promising future of DDR-targeted drug development.