Clinical outcomes for children with acute myeloid leukemia (AML) have improved minimally during the past 4 decades despite maximally intensive chemotherapy, hematopoietic stem cell transplantation, and optimized supportive care. Chemoresistance and relapse remain major sources of childhood cancer–associated mortality and highlight the need for alternative treatment approaches. The remarkable recent success of humoral and cellular immunotherapies in children and adults with relapsed/refractory B-acute lymphoblastic leukemia has inspired hope for similar accomplishments in patients with AML. However, unique challenges exist, including the biologic and immunophenotypic heterogeneity of childhood AML and the significant potential for on-target/off-tumor immunotherapeutic toxicity due to target antigen expression on nonmalignant cells. This article reviews the current landscape of antibody-based and cellular immunotherapies under current clinical evaluation with an emphasis on active or soon-to-open phase 1 trials for children with relapsed/refractory AML.