Obese adipose tissue (AT) is associated with chronic inflammation, and we hypothesized that the keratinocyte-derived chemokine (KC), the mouse ortholog of human interleukin-8, plays a role in obesity-mediated AT inflammation and the subsequent manifestation of insulin resistance. KC expression is increased in the AT and plasma of genetically (ob/ob) and high fat diet-induced obese mouse models, and this increase may be mediated by the elevated leptin and tumor necrosis factor-alpha levels associated with obesity. Obesity-induced KC expression occurs primarily in stromal vascular cells and not in adipocytes, and it is high in preadipocytes and decreases during adipogenesis. Although KC has no effect on adipogenesis, it induces adipocyte expression of inflammatory factors and the insulin resistance mediator, suppressor of cytokine signaling 3. Using chimeric mice deficient in the KC receptor CXCR2 in their bone marrow, we show that the lack of CXCR2 in hematopoietic cells is sufficient to protect from adipose and skeletal muscle macrophage recruitment and development of insulin resistance in diet-induced obese mice. These studies suggest that KC and its receptor CXCR2 are potential targets for the development of new therapeutic approaches for treatment of obesity-related insulin resistance, type II diabetes, and related cardiovascular diseases.