Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer. Treatment has improved but relapsed ALL remains more common than new cases of many ‘common’ paediatric malignancies. We have salvage regimens with substantial complete remission (CR) rates and increasing access to haematopoietic stem cell transplantation, but most patients who relapse die. We need better therapies. Insights into pharmacology may guide more effective use of existing agents. Novel agents with activity against resistant lymphoblasts offer an appealing strategy. However, most candidate agents fail, despite enthusiastic investigators, intriguing mechanisms of action and ‘compelling’ preclinical data. A number of existing combinations provide a 40% complete response rate in second or third relapse. Yet survival in third remission is <10%. Novel agents must, most likely, be integrated into multiagent combinations that provide a higher CR rate or better quality CR's than our conventional combinations in order to contribute substantially to cure. The march from bench to bedside requires careful consideration of the intermediate steps.