Over the past 3 decades, enormous advances have been made in the creation of a standardized treatment protocol for Wilms' tumor. Less morbid regimens for low-risk patients and more efficacious aggressive treatment protocols for high-risk patients have been developed, and continue to be improved with newer studies, such as the NWTS-V. An area that has posed a more challenging aspect of the disease is its relapse. Although a standard follow-up protocol has been produced by in-depth evaluation of previous works, there has been a great deal of difficulty demonstrating improved relapse-free and overall survival rates in re-treatment of children suffering from recurrent Wilms' tumor. Several factors are involved in the success of treatment of relapse, some of which include prerelapse treatment of initial disease and stage, site, and timing of recurrence. New agents and their combination with chemotherapeutics that already have established efficacy are being used for treatment of Wilms' tumor relapse, with varying success. These studies should lead the way for newer investigations in the future. Patients with anaplastic disease, rhabdoid tumors, and clear cell sarcoma are especially in need of these future investigations. Perhaps the true final frontier is establishing the likelihood of patients suffering a relapse. This topic currently is being studied in the fields of biologic markers and gene expression. This knowledge will hopefully, in turn, tailor initial treatment in a more specific manner.