Failure to prevent adult weight gain is associated with an elevated risk for breast cancer. In general, an increase in body weight is accounted for by excess energy intake relative to energy expenditure. Efforts to control weight gain usually involve either a reduction in energy intake via dietary energy restriction (DER), an increase in energy expenditure via physical activity (PA), or both. However, it is not clear whether preventing weight gain by DER, PA, or their combination has comparable effects on the risk for cancer. Results from preclinical models indicate that DER results in a highly reproducible and dose-dependent inhibition of experimentally induced breast cancer. PA also inhibits mammary carcinogenesis, but whether these effects depend on energy balance is not clear. Emerging evidence indicates that reduced levels of circulating insulin-like growth factor (IGF) 1 (IGF-1) and elevated levels of corticosterone may be involved in DER-mediated protection against cancer; however, conditions of PA reported to protect against cancer can actually increase circulating levels of IGF-1. Mechanistic studies have shown that DER inhibits cell proliferation, creates a proapoptotic environment, and reduces blood vessel density adjacent to premalignant and malignant mammary pathologies; comparable information is not available from preclinical studies of PA and carcinogenesis. Additional research is needed to investigate the equivalence of DER, PA, and their combination in breast cancer prevention under comparable conditions of energy balance.