Although outcomes of children and adolescents with newly diagnosed acute myeloid leukemia (AML) have improved significantly over the past two decades, more than one-third of patients continue to relapse and experience suboptimal long-term outcomes. Given the small numbers of patients with relapsed AML and historical logistical barriers to international collaboration including poor trial funding and drug availability, the management of AML relapse has varied among pediatric oncology cooperative groups with several salvage regimens utilized and a lack of universally defined response criteria. The landscape of relapsed pediatric AML treatment is changing rapidly, however, as the international AML community harnesses collective knowledge and resources to characterize the genetic and immunophenotypic heterogeneity of relapsed disease, identify biological targets of interest within specific AML subtypes, develop new precision medicine approaches for collaborative investigation in early-phase clinical trials, and tackle challenges of universal drug access across the globe. This review provides a comprehensive overview of progress achieved to date in the treatment of pediatric patients with relapsed AML and highlights modern, state-of-the-art therapeutic approaches under active and emerging clinical investigation that have been facilitated by international collaboration among academic pediatric oncologists, laboratory scientists, regulatory agencies, pharmaceutical partners, cancer research sponsors, and patient advocates.