Target validation is the basis of drug discovery, yet it too often proceeds without deep mechanistic understanding, limiting the translation of promising discoveries into effective therapies. In this talk, I will share our latest insights into epigenetic vulnerabilities in glioblastoma, focusing on the histone demethylase KDM4 and the histone methyltransferase PRDM9. Using integrated multi-omics and functional approaches, we uncovered how these regulators shape - or sometimes do not shape - glioblastoma growth and drug tolerance. Beyond these findings, I will discuss guiding principles for rigorous, mechanism-based target validation to strengthen preclinical cancer research and improve success rates in clinical translation. Ultimately, precision in target validation is not just good science, it is the key early step in transforming discovery into lasting impact for patients.