Non-small cell lung cancer represents a collection of many clinically, pathologically and molecularly distinct diseases. Identification of molecular drivers in individual tumours and treatment with effective targeted therapy is essential for personalised medicine in lung cancer. Rearrangements in the Anaplastic Lymphoma Kinase (ALK) gene are present in 3-5% of patients with NSCLC – typically in younger, never smokers with adenocarcinoma histology. Patients with ALK rearranged lung cancers demonstrate high response rates and prolonged progression free survival after treatment with ALK inhibitors including crizotinib, ceritinib and alectinib. Two phase III trials that demonstrated the superiority of crizotinib over chemotherapy have established therapy with ALK inhibitors as standard of care for patients with ALK rearranged lung cancer indicating that, after EGFR mutations, ALK represent the second molecular target in NSCLC to be validated through phase III clinical trials. Other molecular alterations in NSCLC such as ROS1 gene rearrangements are present in 1-2% of lung cancer patients. Whilst single arm clinical trials have demonstrated impressive efficacy of crizotinib in ROS1 rearranged NSCLC – it is unlikely that it will be possible to conduct a phase III study in this uncommon molecularly-defined population highlighting the challenges in the design and conduct of trials leading to regulatory approval of drugs active in populations with rare molecular drivers.