Obesity is responsible for the mounting incidence of metabolic disease in adult and pediatric populations. Understanding of the pathogenesis and maintenance of the obese state has advanced rapidly over the past 10 years. Bodily energy reserves are managed actively by complex systems that regulate food intake, substrate partitioning, and energy expenditure. An underlying assumption that circulating factors released from storage organs were able to signal bodily energy reserves was confirmed with the discovery of the leptin system. This proof of concept has spurred on the discovery of a multitude of other adipocyte-generated factors. These circulating factors signal to the brain and other organs of metabolic importance, including adipose tissue, liver, muscle, and the immune system. Adipose-derived factors have numerous implications for the basic biology of obesity and provide prospective targets for the amelioration of obesity and its adverse metabolic consequences. In this review we detail the current understanding of leptin as a prototypical adipose tissue-derived hormone related to appetite and obesity. We also describe other important adipose-derived factors in relation to their metabolic effect.