Although platinum-based chemotherapy is the standard of care for most cases of advanced lung adenocarcinoma, its effectiveness is limited by the frequent incidence of innate chemoresistance. As a result, response rates rarely exceed 20%, even though cis-platinum and carboplatin are highly effective in other settings such as small cell lung, ovarian and testicular cancers. We hypothesized that innate chemoresistance in lung adenocarcinoma is mediated by one or more signalling pathways dependent on the expression of a single gene, and that these pathways could ultimately be targeted therapeutically. To address this question, we developed a synthetic-lethal high throughput siRNA screen using the innately resistant A549 lung adenocarcinoma cell line. Optimisation of the screen was performed using an siRNA death control (PLK1), which induced cell death in the absence of platinum, and a sensitization control (MTOR), which enhanced cell death only in combination with a sublethal concentration of carboplatin. These independent controls revealed that the screening protocol performed within acceptable limits of variability, quality and reproducibility as determined by Z’ factor analysis. Screening was then performed using a pool of four siRNAs targeting a single gene in conjunction with vehicle treatment, or with carboplatin. After screening siRNAs targeting the 720 kinases and 256 phosphatases of the human genome, we identified 50 candidate targets based on fold change difference between platinum and vehicle treatments, and statistical significance determined by multiple t-test corrected for false discovery rate. Preliminary pathway analysis revealed a highly significant enrichment for genes in the MAPK pathway. These data demonstrate that a synthetic-lethal approach can be used to identify therapeutic targets that could potentially sensitize lung adenocarcinoma to platinum-based chemotherapy.