Advances in pediatric cancer treatment represent one of modern medicine’s greatest achievements. This progress would not be possible without testing new therapies in children. However, pediatric research must satisfy stricter ethical and regulatory standards than research with adults, in light of children’s inability to provide consent. We contend that current approaches to approving phase 1 pediatric cancer trials may inappropriately hinge on perceptions of therapeutic benefit without adequate consideration of the unlikelihood of such benefit in many cases and the magnitude of associated risks. Although such research is critically important, steps should be taken to maximize the prospect of direct benefit to enrolled children and to use alternative approval pathways for clinical trials that are socially valuable but unlikely to offer direct benefit to the pediatric participants.