Sex differences exist in the regulation of energy homeostasis. Better understanding of the underlying mechanisms for sexual dimorphism in energy balance may facilitate development of gender-specific therapies for human diseases, e.g. obesity. Multiple organs, including the brain, liver, fat and muscle, play important roles in the regulations of feeding behavior, energy expenditure and physical activity, which therefore contribute to the maintenance of energy balance. It has been increasingly appreciated that this multi-organ system is under different regulations in male vs. female animals. Much of effort has been focused on roles of sex hormones (including androgens, estrogens and progesterone) and sex chromosomes in this sex-specific regulation of energy balance. Emerging evidence also indicates that other factors (not sex hormones/receptors and not encoded by the sex chromosomes) exist to regulate energy homeostasis differentially in males vs. females. In this review, we summarize factors and signals that have been shown to regulate energy homeostasis in a sexually dimorphic fashion and propose a framework where these factors and signals may be integrated to mediate sex differences in energy homeostasis.