Obesity is accompanied by chronic, low-grade inflammation of adipose tissue, which promotes insulin resistance and type-2 diabetes. How does fat inflammation escape the powerful armamentarium of cells and molecules normally responsible for guarding against a run-away immune response? Regulatory CD4+ T cells expressing the transcription factor Foxp3 (termed Treg cells) are a lymphocyte lineage specialized in controlling immunologic reactivity. Treg cells with a unique phenotype were highly enriched in the abdominal fat of normal mice, but were strikingly and specifically reduced at this site in insulin-resistant models of obesity. In loss-of-function and gain-of-function experiments, Treg cells regulated the inflammatory state of adipose tissue and insulin resistance. Cytokines differentially synthesized by fat-resident regulatory and conventional T cells directly impacted on the synthesis of inflammatory mediators and glucose uptake by cultured adipocytes. These findings open the door to harnessing the anti-inflammatory properties of Treg cells to inhibit elements of the metabolic syndrome.