The discovery of druggable mutations in non-small cell lung cancer (NSCLC) has revolutionised the treatment of these patients. A prime example of this consists of targeting the constitutively activated ROS1 kinase in patients harbouring a genetic ROS1 rearrangement. In 2016, the multikinase tyrosine kinase inhibitor (TKI) crizotinib became the first targeted treatment option for patients with advanced ROS1-positive NSCLC. Unfortunately, however, crizotinib comes with some important drawbacks. First of all, the reduced central nervous system (CNS) penetration of crizotinib makes it unsuitable for patients with metastases in the CNS, a very common finding in ROS1-rearranged NSCLC. This lack of intracranial activity also leads to an increased risk for the development of new CNS lesions. In addition to this, acquired mutations in ROS1 often render patients who initially have a good response, resistant to crizotinib. To address these issue, several new highly potent and CNS penetrant ROS1 inhibitors have been developed (i.e. entrectinib, lorlatinib, repotrectinib), with several studies highlighting their potential as a frontline treatment for patients with advanced ROS1-rearranged NSCLC. Recently, entrectinib became the first of these next-generation ROS1 inhibitors to receive approval by the European Commission for the treatment of ROS1-rearranged advanced NSCLC patients who did not yet receive a ROS1 targeting agent.