Under and overweight, usually secondary to energy imbalance, are common complications of childhood chronic disease. A simple energy balance paradigm has been helpful in understanding the etiology of underweight and overweight in chronic disease, including malignant disease, particularly when measurements of total energy expenditure have been made using the doubly labeled water method. Measurements of energy intake are usually insufficiently accurate and precise to be informative, and measurements of energy expended at rest alone provide an incomplete and potentially misleading assessment of energy expenditure and the causes of energy imbalance. In some diseases, such as acute lymphoblastic leukemia, the natural history and etiology of energy imbalance are now particularly well understood. Recent improvements in our understanding of etiology should lead to improved strategies for the prevention and treatment of underweight and overweight in chronic disease. In some diseases, cachectic processes drive the development of underweight: these are partly independent of energy balance, and strategies for prevention and treatment may require approaches aimed at modifying the cachectic process rather than attempting to modify energy balance directly. Pediatr Blood Cancer © 2007 Wiley-Liss, Inc.