High-throughput drug screens in cancer cell lines test compounds at low concentrations, thereby enablingthe identification of drug-sensitivity biomarkers, while resistance biomarkers remain underexplored. Dissect-ing meaningful drug responses at high concentrations is challenging due to cytotoxicity, i.e., off-target ef-fects, thus limiting resistance biomarker discovery to frequently mutated cancer genes. To address this,we interrogate subpopulations carrying sensitivity biomarkers and consecutively investigate unexpectedlyresistant (UNRES) cell lines for unique genetic alterations that may drive resistance. By analyzing theGDSC and CTRP datasets, we find 53 and 35 UNRES cases, respectively. For 24 and 28 of them, we highlightputative resistance biomarkers. We find clinically relevant cases such as EGFRT790Mmutation in NCI-H1975or PTEN loss in NCI-H1650 cells, in lung adenocarcinoma treated with EGFR inhibitors. Interrogating the un-derpinnings of drug resistance with publicly available CRISPR phenotypic assays assists in prioritizing resis-tance drivers, offering hypotheses for drug combinations.