Background: Hard-to-treat childhood cancers are those where standard treatment options do not exist and prognosis is poor. Healthcare professionals (HCPs) are responsible for communicating with families about prognosis and complex experimental treatment. We aimed to identify HCPs’ key challenges and skills required when communicating with families about hard-to-treat cancers, and their perceptions of communication-related training. Method: We interviewed Australian HCPs who had direct responsibilities in managing children/adolescents with a hard-to-treat cancer within the past 24 months. Interviews were analysed using qualitative content analysis. Results: We interviewed 10 oncologists, 7 nurses, and 3 social workers. HCPs identified several challenges for communication with families including: balancing information provision while maintaining realistic hope; managing their own uncertainty; and nurses and social workers being under-utilised during conversations with families, despite widespread preferences for multidisciplinary teamwork. HCPs perceived that making themselves available to families, empowering them to ask questions, and repeating information helped to establish and maintain trusting relationships with families. Half the HCPs reported receiving no formal training for communicating prognosis and treatment options with families of children with hard-to-treat cancers. Nurses, social workers, and junior oncologists supported the development of communication training resources, more so than senior oncologists. Conclusion(s): Resources are needed which support HCPs to communicate with families of children with hard-to-treat cancers. Such resources may be particularly beneficial for junior oncologists and other HCPs during their training, and should aim to prepare them for common challenges, and to foster greater multidisciplinary collaboration.