Therapeutic resistance is the leading cause of cancer-related mortalities, thus urging the development of more effective treatments for refractory tumors. Drug repurposing, which consists in using existing drugs for new medical indications represents a promising strategy to fast-track novel drug combinations in cancer. However, to increase the success rate in clinical trial of novel therapeutic options, it is essential to fully unravel their molecular mechanisms ofaction. We recently developed an innovative approach, termed reverse molecular pharmacology, which consists in deciphering the poly-pharmacology of existing drugs (either approved or in clinical development) to unveil disease-relevant targetable vulnerabilities. This strategy is based on pharmaco-proteomics to reveal the interactome of drugs within tumor cells. We applied our original method to beta-blockers in the pediatric cancer, neuroblastoma, and to anti-helminthics in brain tumors. This revealed the unsuspected role of the heme biosynthesis pathway in neuroblastoma chemoresistance and that of the methylosome in glioblastoma. Our integrated approach thus highlighted novel targetable vulnerabilities in these hard-to-treat cancers, thus opening potential avenues to improve treatments and patient outcome.