Genetic interactions play crucial roles in cell-essential functions. Intrinsic genetic defects in tumors typically involve gain-of- and loss-of-function mutations in tumor suppressor genes (TSGs) and oncogenes, respectively, providing potential antitumor vulnerabilities. Moreover, tumor cells with TSG deficiencies exhibit heightened sensitivity to the inhibition of compensatory pathways. Synthetic and collateral lethality are two strategies used for exploiting novel drug targets in multiple types of cancer. Collateral lethality is a unique type of synthetic lethality that occurs when passenger genes are co-deleted in neighboring TSGs. Although synthetic lethality has already been successfully demonstrated in clinical practice, antitumor therapeutics based on collateral lethality are predominantly still in the preclinical phase. Therefore, screening for potential genetic interactions within the cancer genome has emerged as a promising approach for drug development. Here, the two conceptual therapeutic strategies that involve the deletion or inactivation of cancer-specific TSGs are discussed. Moreover, existing approaches for screening and identifying potential gene partners are also discussed. Particularly, this review highlights the current advances of "collateral lethality" in the preclinical phase and addresses the challenges involved in translating them into therapeutic applications. This review provides insights into these strategies as new opportunities for the development of personalized antitumor therapies.Copyright © 2024 Elsevier Inc. All rights reserved.