Clinical trials have underpinned progress in the treatment of cancer in childhood: about 75% of children newly diagnosed with cancer can expect to be long-term survivors. This success has been achieved because most children with cancer have participated in available clinical trials. This high level of engagement of the childhood-cancer community relies on the so-called therapeutic alliance that begins between doctors and families when a child is diagnosed with cancer. More research is needed to understand how to present most effectively the unfamiliar idea of a randomised clinical trial at a stressful time. High overall survival using current regimens presents challenges for future trial design-to secure further incremental increases in survival or to show survival equivalence from targeted agents that might have reduced side-effects. Small subgroups of children with cancers defined by molecular signatures mean that international recruitment is essential to do trials in a reasonable timeframe. Such collaboration across linguistic and cultural boundaries presents not only legal and regulatory hurdles, but also challenges the childhood-cancer research community to reappraise individual treatment preferences. The introduction of new paediatric regulations in Canada and the USA and Europe should encourage manufacturers of new anticancer drugs to lend support to clinical trials of cancer in childhood.