Overweight and obese individuals frequently restrict caloric intake to lose weight. The resultant weight loss, however, typically is followed by an equal or greater weight gain, a phenomenon called weight cycling. Most attention to weight cycling has focused on identifying its detrimental effects, but preclinical experiments indicating that intermittent caloric restriction or fasting can reduce cancer risk have raised interest in potential benefits of weight cycling. Although hypothesized adverse effects of weight cycling on energy metabolism remain largely unsubstantiated, there is also a lack of epidemiologic evidence that intentional weight loss followed by regain of weight affects chronic-disease risk. In the limited studies of weight cycling and cancer, no independent effect on postmenopausal breast cancer but a modest enhancement of risk for renal cell carcinoma, endometrial cancer, and non-Hodgkin's lymphoma have been reported. An effect of either intermittent caloric restriction or fasting in protecting against cancer is not supported by the majority of rodent carcinogenesis experiments. Collectively, the data argue against weight cycling and indicate that the objective of energy balance-based approaches to reduce cancer risk should be to strive to prevent adult weight gain and maintain body weight within the normal range defined by body mass index.