Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that acts as an oncogenic driver in solid and haematological malignancies in both children and adults. Although ALK-expressing (ALK) tumours show strong initial responses to the series of ALK inhibitors currently available, many patients will develop resistance. In this Review, we discuss recent advances in ALK oncogenic signalling, together with existing and promising new modalities to treat ALK-driven tumours, including currently approved ALK-directed therapies, namely tyrosine kinase inhibitors, and novel approaches such as ALK-specific immune therapies. Although ALK inhibitors have changed the management and clinical history of ALK tumours, they are still insufficient to cure most of the patients. Therefore, more effort is needed to further improve outcomes and prevent the tumour resistance, recurrence and metastatic spread that many patients with ALK tumours experience. Here, we outline how a multipronged approach directed against ALK and other essential pathways that sustain the persistence of ALK tumours, together with potent or specific immunotherapies, could achieve this goal. We envision that the lessons learned from treating ALK tumours in the clinic could ultimately accelerate the implementation of innovative combination therapies to treat tumours driven by other tyrosine kinases or oncogenes with similar properties.