The future of pediatric oncology will be influenced by changes in drug design and treatment strategy, with genomic medicine and molecular-based diagnostics and therapeutics playing increasingly important roles. The role of imaging as a means of measuring response to therapy has also evolved, with the development of new technologies and higher sensitivity means of detecting tumors. Conventional anatomical imaging techniques are being increasingly supplemented with functional techniques, including FDG-PET imaging and diffusion-weighted MR imaging. The risk-adapted treatment regimens of the past, which led to improved event-free and overall survival in many pediatric cancers, have paved the way for new response-based treatment paradigms. Response-based approaches seek to identify patients with a high likelihood of cure, treating them less aggressively, while those not responding to therapy are identified early and redirected into more aggressive therapeutic regimens. These advances will require concurrent development of imaging biomarkers as surrogates of early response to therapy. Incorporating these techniques into new response-directed treatment algorithms will be crucial as personalized medicine and molecular-targeted, tumor-specific therapies gain acceptance for the treatment of children with cancer.