Adipose tissue macrophage (ATM) accumulation through C-C motif chemokine receptor 2 (CCR2) and its ligand monocyte chemoattractant protein-1 (MCP-1) is considered pivotal in the development of insulin resistance. However, our new study has demonstrated that CCR5, a different CC chemokine receptor, plays an important role in the ATM recruitment and activation and subsequent development of insulin resistance (see the recent article in Diabetes). Although recent human studies have shown upregulation of the expression of not only MCP-1-CCR2 but also other CC chemokines and their receptors in the visceral fat of obese individuals, it is not known if CCR5 is involved in ATM recruitment and insulin resistance. This article has shown several new important observations. First, expression of CCR5 and its ligands is significantly increased and is equal to that of CCR2 and its ligands in the white adipose tissue (WAT) of obese mice, particularly in the macrophage fraction. Second, fluorescence-activated cell sorter analysis clearly demonstrates a robust increase in accumulation of CCR5+ ATMs in response to a high fat (HF) diet. Third, and most important, two distinct models, both Ccr5-/- mice and chimeric mice lacking CCR5 only in myeloid cells, are protected from insulin resistance and diabetes through reduction in ATM accumulation. Finally, it is interesting that an alternatively activated, M2-dominant shift in ATM is induced in obese Ccr5-/- mice. Taken together, these data indicate that CCR5 is a novel link between obesity, adipose tissue inflammation, and insulin resistance.