Over the past 50 years, numerous advances in treatment have produced dramatic increases in the cure rates of pediatric leukemias. Despite this progress, the majority of children with relapsed leukemia are not expected to survive. With current chemotherapy regimens, approximately 15 % of children with acute lymphoblastic leukemia and 45 % of children with acute myeloid leukemia will have refractory disease or experience a relapse. Advances in the treatment of pediatric relapsed leukemia have not mirrored the successes of upfront therapy, and newer treatments are desperately needed in order to improve survival in these challenging patients. Recent improvements in our knowledge of cancer biology have revealed an extensive number of targets that have the potential to be exploited for anticancer therapy. These advances have led to the development of a number of new treatments that are now being explored in children with relapsed or refractory leukemia. Novel agents seek to exploit the same molecular aberrations that contribute to leukemia development and resistance to therapy. Newer classes of drugs, including monoclonal antibodies, tyrosine kinase inhibitors and epigenetic modifiers are transforming the treatment of patients who are not cured with conventional therapies. As the side effects of many new agents are distinct from those seen with conventional chemotherapy, these treatments are often explored in combination with each other or combined with conventional treatment regimens. This review discusses the biological rationale for the most promising new agents and the results of recent studies conducted in pediatric patients with relapsed leukemia.