Biologicals are defined as agents that are either uniquely or partially tumor-specific. Great expectations were raised by the success in agents that target a specific genetic translocation: all-trans retinoic acid, targeting the chronic myeloid leukemia retinoic acid receptor in acute promyelocytic leukemia and imatinib, a small molecule targeting the BCR-ABL translocation in chronic myeloid leukemia (CML). Thus far, the search for similar “druggable” genetic targets in pediatric cancers has not yet resulted in such dramatic results. The rarity of pediatric cancer as well as ethical considerations necessitate that the agents for testing be carefully and rigorously selected. Biologicals present an additional challenge, as they often do not lend themselves to in vitro testing. Early approaches to specific targeting of solid tumors utilized monoclonal antibodies. The microenvironment provides an interesting new biological approach to treating tumors and alteration of the host immune response provides another avenue. Biological agents are a step forward in supportive care to reduce the hematological toxicity of high-dose chemotherapy and to manage the frequent infectious complications.