Genomic instability (GI), characterized by substantial alterations in the genetic repository of cells, has been known to contribute to the development of various types of cancers and emerged as a viable target. Translational research has demonstrated the promise of GI-targeted therapeutic approaches for treating various types of cancers. The Food and Drug Administration (FDA), USA, has approved some of the GI-targeted molecules for use in clinics, such as poly (ADP-ribose) polymerase (PARP) inhibitors (e.g., Olaparib, Rucaparib, etc.) in BRCA1/2-, HER-2-mutated breast, and HRD-mutated ovarian cancers, and many are in preclinical phases. However, the obstacles such as off-target effects, development of resistance along with identification of precise target patient populations, and lack of precise prognostic biomarkers limit their broader applications. The integration of GI-targeted treatments with conventional therapeutics (e.g., PARP inhibitors along with chemotherapy) also holds promise for clinical use. The future of GI-targeted medicines involves the integration of genomic data with artificial intelligence to create tumor-specific, tailored treatments, thereby improving precision and patient outcomes.