Despite significant survival improvements in multiple pediatric malignancies, the prognosis is very dismal for relapsed and metastatic pediatric tumors. The event-free survival (EFS) for metastatic neuroblastoma and sarcoma in children is 40% and relapsed/refractory EFS is <20%. Glioblastoma multiforme continues to have a dismal EFS (<25%). Children with acute myeloid leukemia in specific subgroups with estimated overall survival (OS) is ≤25%. The overall mortality of the relapsed or progressed children with non-Hodgkin’s lymphoma such as Burkitt Lymphoma or diffuse large B cell lymphoma following treatment is high and the 1- and 2-year EFS rates are approximately 40% and 20%, respectively. These facts underscore the unmet medical need in these high-risk patients. Long-term control of these high-risk diseases cannot be achieved by a single therapeutic agent. Combinatorial targeted immunotherapies show promising outcomes in pre-clinical and clinical studies. This collection will focus on the new and emerging methods of combinatorial immunotherapies and the in vitro and in vivo models that are currently being explored for high-risk pediatric cancers. These methods will include but are not limited to the combinations of adoptive cellular therapies with novel antibodies, cytokines, and oncolytic viral therapies.