Changes in therapy, primarily intensification, for childhood leukemias have significantly improved cure rates during the past 30 years. The increasing number of survivors has led to a heightened appreciation of the late complications of treatment caused by both radiation and chemotherapy. Important late effects include decreased growth, poor school performance, altered cardiac function, infertility, and second malignant neoplasms. The long term outcome of children and adolescents suffering from the most recently recognized acute complication of treatment, avascular necrosis of weight-bearing bones, is still not known. These, and all patients treated on clinical trials, should be followed throughout their lives. Many of the complications of treatment are often not realized until years after the completion of therapy; some have been found to be related to dose intensity, emphasizing the importance of clinical trials that examine reduction of therapy for diseases with excellent cure rates. A successful example of this strategy is the elimination or reduction of radiation dose for the prevention of central nervous system acute lymphocytic leukemia. This has resulted in fewer long term central nervous system complications without a decrease in survival rates. As knowledge of late effects increases, design of future trials will need to focus on striking a balance between cure and long term toxicity.