Insulin resistance is associated with many common diseases including diabetes mellitus, hyperlipidemia and hypertension, and plays an important role for determining their clinical courses. Obesity is a multifactorial syndrome characterized by an excessive adipose tissue accumulation, and is associated with acquired insulin resistance. Adipose tissue, acting as one of the endocrine organs, has been revealed to produce and secrete some bioactive molecules, "adipocytokines", which regulate cell growth and/or metabolic pathways. Tumor necrosis factor(TNF)-alpha is also synthesized by adipocytes, and is involved in the expression of peripheral insulin resistance. This review deals with molecular mechanisms of the TNF/TNF receptor system promoting insulin resistance, and its prevention by the insulin-sensitizing drugs, thiazolidinediones.