Although childhood Hodgkin disease is sensitive to the treatment regimens devised for Hodgkin disease in adults, long-term toxicity is enhanced in the developing individual. As a result, there have been dual goals in the design of clinical trials for pediatric Hodgkin disease: 1) to reduce long-term organ injury; and 2) to increase efficacy. Radiation dose and field has been reduced by enhanced reliance on chemotherapy, thus limiting the risks of hypoplasia, hypothyroidism, secondary cancers, and valvular and atherosclerotic heart disease. Multiagent, chemotherapeutic regimens for children have been developed to avoid the risks of sterility, leukemia, and cardiopulmonary toxicity. Newer approaches advocate for early dose intensity to limit cumulative therapy using response-based paradigms. Targeting molecular mechanisms specific for the Reed-Sternberg cell may allow for less toxic and more efficacious treatments in the future.