Lung cancer is the commonest cause of cancer death worldwide with a five-year survival rate of less than five percent for metastatic tumours. Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancer cases of which adenocarcinoma prevails. Patients almost invariably develop metastatic drug-resistant disease and this is responsible for our failure to provide curative therapy. Hence, a better understanding of the mechanisms underlying these biological processes is urgently required to improve clinical outcome. The p90 (90 kDa) Ribosomal Protein S6 Kinases (RSKs) are downstream effectors of the RAS/MAPK cascade. RSKs are highly conserved serine/threonine protein kinases implicated in diverse cellular processes, including cell survival, proliferation, migration and invasion. There are four human isoforms (RSK1-4), which are uniquely characterised by the presence of two non-identical N- and C-terminal kinase domains. RSK isoforms are 73%-80% identical at the protein level and this has been thought to suggest overlapping functions. However, through functional genomic kinome screens, we show that RSK4, contrary to RSK1, promotes both drug resistance and metastasis in lung cancer. RSK4 is overexpressed in the majority of NSCLC biopsies and this correlates with poor overall survival in lung adenocarcinoma patients. Genetic silencing of RSK4 sensitises lung cancer cells to chemotherapy and prevents their migration and invasiveness in vitro and in vivo. This is associated with downregulation of the anti-apoptotic proteins c-IAP1 and c-IAP2, and induction of mesenchymal-epithelial transition (MET), respectively. A small-molecule inhibitor screen identified several floxacins as potent allosteric inhibitors of RSK4 activation. Trovafloxacin reproduced all biological and molecular effects of RSK4 silencing in vitro and in vivo and it is predicted to bind a novel allosteric site as revealed by our RSK4 N-terminal kinase domain crystal structure and mathematical Markov Transient Analysis. Taken together, our data implicate RSK4 as a promising novel therapeutic target in lung cancer.