The Second International Conference on Immunotherapy in Pediatric Oncology was held in Houston, Texas, USA, October 11-12, 2010, to discuss the progress and challenges that have occurred in cutting edge immunotherapeutic strategies currently being developed for pediatric oncology. Major topics included immune targeting of acute lymphoblastic leukemia and pediatric solid tumors, chimeric antigen receptors (CARs) for hematologic malignancies and solid tumors, enhancing graft-versus-leukemia for pediatric cancers, overcoming hurdles of immunotherapy, strategies to active the innate immune system, and moving immunotherapy beyond phase I studies. Significant progress has been made in the last 2 years both in the development of novel immunobiologics such as CARs, and in establishing survival benefits of an anti-GD2 monoclonal antibody in randomized studies. Although there is much excitement going forward, a great deal of laboratory and regulatory challenges lie ahead in improving the efficacy of each of these modalities as well as getting them to patients in a timely and cost-effective fashion. The resulting discussions will hopefully lead to new collaborations and insight for further translational and clinical studies.