The maintenance of appetite at proper levels, depending on the energy status, is important; otherwise abnormal appetite may cause a series of disorders, such as anorexia, hyperphagia, obesity, and its complications (diabetes mellitus, hypertension, cardiovascular disease, and fatty liver disease). Hypothalamic AMPactivated protein kinase (AMPK) integrates diverse hormonal and nutritional signals to regulate food intake and energy metabolism. Recent evidence suggests that different hormones, nutrients and synthetic chemicals can modulate AMPK activity in the hypothalamus, thereby regulating food intake and body weight, through neuropeptide expressions. In order to elucidate the mechanisms that control hypothalamic AMPK activity, a variety of studies have focused on finding upstream and downstream modulators of hypothalamic AMPK for the regulation of food intake and energy balance. This review highlights the current evidence for understanding how hypothalamic AMPK regulates food intake and energy balance, and will help in the development of effective interventions for the treatment of food intake-related disorders. In the future, it is hoped that new pharmaceutical developments targeting hypothalamic AMPK, in combination with careful clinical trials, will lead to improved and effective therapeutic strategies for complications caused by abnormal appetite and energy balance.