The prevalence of obesity, an established epidemiologic risk factor for many cancers, has risen steadily for the past several decades in the U.S. Particularly alarming are the increasing rates of obesity among children, portending continuing increases in the rates of obesity and obesity-related cancers for many years to come. Unfortunately, the mechanisms underlying the association between obesity and cancer are not well understood. In particular, the effects and mechanistic targets of interventions that modulate energy balance, such as reduced calorie diets and physical activity, on the carcinogenesis process have not been well characterized. The purpose of this review is to provide a strong foundation for future mechanistic-based research in this area by describing key animal and human studies of energy balance modulations involving diet, exercise, or pharmaceutical agents and by focusing on the interrelated pathways affected by alterations in energy balance. Particular attention in this review is placed on the components of the insulin/IGF-1/Akt pathway, which has emerged as a predominant target for disrupting the obesity-cancer link. Also discussed is the promise of global approaches, including genomics, proteomics, and metabolomics, for the elucidation of energy balance-responsive pathways. The ultimate goal of this work is to provide the missing mechanistic information necessary to identify targets for the prevention and control of cancers related to or caused by excess body weight.