Lung cancer remains one of the most complex and challenging cancers, being responsible for almost a third of all cancer deaths. This grim picture seems however to be changing, for at least a subset of lung cancers. The number of patients who can benefit from targeted therapies is steadily increasing thanks to the progress made in identifying actionable driver lesions in lung tumours. The success of the latest generation of EGFR and ALK inhibitors in the clinic not only illustrates the value of targeted therapies, but also shows how almost inevitably drug resistance develops. Therefore, more sophisticated approaches are needed to achieve long-term remissions. Although there are still significant barriers to be overcome, technological advances in early detection of relevant mutations and the opportunity to test new drugs in predictive preclinical models justify the hope that we will overcome these obstacles.