Acquired resistance to therapy with tyrosine kinase inhibitors (TKIs) is common in patients with ALK or ROS1-rearranged non-small-cell lung cancer (NSCLC). Lorlatinib is a novel TKI of both ALK and ROS1 specifically designed to inhibit mutations driving resistance to other ALK TKIs, and to penetrate the blood–brain barrier. A phase I dose-escalation study of this TKI was conducted in 54 patients with NSCLC and disease progression after receiving other TKIs. An objective response was observed in 46% of patients with ALK rearrangements, 50% of patients with ROS1 rearrangements, and 42% of patients who had received two or more TKIs. The most common treatment-related adverse events were hypercholesterolaemia (72%), hypertriglyceridaemia (39%), peripheral neuropathy (39%), and peripheral oedema (39%). Lorlatinib is currently being compared with crizotinib in the frontline in a phase III randomized trial in patients with ALK-rearranged NSCLC.