Wilms tumor, or nephroblastoma, has provided a paradigm for progressive improvement in clinical outcomes achieved through serial cooperative group studies. With modern surgery, chemotherapy, and radiation therapy approaches, the overall survival rate for patients with Wilms tumor has reached 90%. Remarkably, the increase in survival has been achieved with a reduction in therapy for most patient subgroups, leading not only to more survivors, but also to healthier survivors. A key contributor to improved outcomes has been the development of clinical and biologic prognostic markers that have enabled risk-directed therapy. Whereas the early cooperative group studies used only tumor stage for risk stratification, current Children's Oncology Group (COG) and International Society of Pediatric Oncology (SIOP) protocols employ a multitude of prognostic factors to guide therapy. Prognostic factors used in the current generation of COG studies include stage, histology, patient age, tumor weight, completeness of lung nodule response, and loss of heterozygosity at chromosomes 1p and 16q. Future COG studies seek to incorporate gain of chromosome 1q and methylation pattern of chromosome 11p15 into the risk classification schema. Prognostic factors used in the current SIOP studies include stage, histology, tumor volume, and responsiveness to therapy. Future SIOP studies seek to incorporate absolute blastemal volume and novel molecular markers for resistant blastema into the risk stratification approach.