Patient-derived tumor organoids can be predictive of patient's treatment responses, and normal tissue-derived organoids allow for drug toxicity testing. Combining both types of organoids therefore enables screening for tumor-specific drug vulnerabilities. Here, we provide a detailed protocol for organoid drug screening using, as proof-of-principle, patient-derived malignant rhabdoid tumor organoids. The protocol can be adapted for drug testing on any tumor and/or normal tissue-derived organoid culture. For complete details on the use and execution of this protocol, please refer to Calandrini et al. (2021).