Obesity, characterized by enhanced food intake (hyperphagia) and reduced energy expenditure that results in the accumulation of body fat, is a major risk factor for various diseases including diabetes, cardiovascular disease and cancer. In the United States, more than half of adults are overweight and this number continues to increase (Flegal et al., 2002). The adipocyte secreted hormone, leptin, and its downstream signaling mediators play crucial roles in the regulation of energy balance. Leptin decreases feeding while increasing energy expenditure and permitting energy-intensive neuroendocrine processes (such as reproduction). Thus, leptin also modulates the neuroendocrine reproductive axis. The gonadal steroid hormone, estrogen, plays a central role in the regulation of reproduction and also contributes to the regulation of energy balance. Estrogen deficiency promotes feeding and weight gain, and estrogen facilitates and to some extent mimics some actions of leptin. In this review, we examine the function of estrogen and leptin in the brain, with a focus on mechanisms by which leptin and estrogen cooperate in the regulation of energy homeostasis.