Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer that is characterised by impressive initial response rates to platinum-based chemotherapy, followed by nearly universal relapse with platinum-resistant disease. Whilst some mechanisms of resistance have been identified, there has been a lack of comprehensive unbiased screening to survey the mechanisms of resistance in SCLC. To address this, we employed an unbiased whole-genome gain-of-function screening approach using CRISPR activation (CRISPRa) to identify genetic drivers of platinum resistance. As a proof of concept, we identified genes associated with glutathione metabolism which has previously been associated with platinum resistance. These genes include solute carrier family 7 member 11 (SLC7A11), a known facilitator of cellular cystine uptake which contributes to glutathione biosynthesis. In addition, we have identified and validated genes controlling biological processes that have not been previously linked to platinum sensitivity. We are currently investigating these targets by whole-transcriptome and protein-protein interactome analyses in platinum resistant and sensitive SCLC cells, with the aim of identifying new therapies to overcome platinum resistance in this devastating disease.