Two types of genetic mutations, gain-of-function in oncogenes and loss-of-function in tumor-suppressor genes, are important molecular bases of tumorigenesis of human cancers. Target-based drug discovery is the main stream of contemporary cancer therapeutic development but largely focuses on gain-of-function mutations in oncogenes. Loss-of-function mutations in tumor-suppressor genes are often neglected as therapeutic targets. In this review, we discuss the feasibility of targeting loss-of-function mutations in tumor-suppressor genes for the identification of cancer-specific therapeutic agents.