The humanitarian system is struggling to adapt to changes in the global political environment, trends in armed conflict and displacement, and advances in science and technology. In recent years, the international community has undertaken a number of efforts to overcome these challenges, such as the Agenda for Humanity, a plan that outlines the changes needed to alleviate suffering, reduce risk, and lessen vulnerability on a global scale. This article reviews recent evidence from a range of disciplines to inform these efforts, especially as they relate to the protection of children. Early childhood and adolescence constitute two critical periods of child development that lay the foundations for future health and wellbeing. Exposure to adversity in crisis contexts can compromise this development, with potentially life-long consequences. Evidence suggests that relationships with caregivers and peers play a central role in mediating childhood experiences of adversity. Unfortunately, interventions for children affected by crises are usually too fragmented to maximize the protective effects of healthy relationships. This article stresses the importance of developing multisectoral and relational interventions capable of promoting healthy development across the life course. Given the central role of caregivers, the household is an especially powerful level of intervention for combining approaches from different sectors. More concerted efforts are needed to develop household interventions that combine traditional sectoral approaches with innovative, cross-cutting measures, such as cash transfers and parental support. Household interventions should also be an integral part of broader community and society level actions, which together form more comprehensive systems of care.