The rapid increase of obese population in the United States has made obesity into epidemic proportion. Obesity is a strong risk factor for metabolic syndrome, type 2 diabetes mellitus, cardiovascular diseases, cancer and other diseases. Compelling evidence has demonstrated that increased adipose tissue mass is not only the consequence of obesity, but also plays a central role in the development of obesity-associated diseases. Recent studies have profoundly changed the concept of adipose tissue from being an energy depot to an active endocrine organ. The development of obesity alters adipocyte-derived hormones or cytokines expression, which provide a link between obesity and impaired insulin sensitivity and metabolic defects in other tissues. This review summarizes the current knowledge on how major adipose-derived hormones or adipocytokines influence insulin sensitivity.