Chemokines and their receptors play a pivotal role in controlling T cell trafficking in immunity and inflammation. Two chemokines, CCL17 and CCL22, activate the chemokine receptor CCR4, expressed on functionally distinct subsets of T cells: cutaneous leukocyte-associated antigen (CLA)+ skin-homing, T helper (Th) 2, and CD25+ T suppressor cells. Here, we compared the ability of CCL17 and CCL22 to promote CCR4 internalization as a mechanism of regulation of receptor function on human Th2 cells. We report that CCL22 is a potent and rapid inducer of CCR4 internalization, while CCL17 is not. CCR4 internalization does not require G protein coupling, while being dependent on lipid rafts integrity and clathrin-coated pits functionality. Cell surface disappearance of CCR4 is rapidly reversed upon removal of exogenous ligand by virtue of receptor recycling. CCR4 internalization leads to a loss of functional responsiveness, while recovery of surface expression leads to re-acquisition of chemotactic sensitivity of Th2 cells. The differential CCR4 desensitization and internalization reported here and the distinct expression patterns of CCL17 and CCL22 observed in vivo suggest that while CCL17 may act first on CCR4 at the endothelial surface to promote vascular recognition, CCL22 could subsequently engage the receptor within the tissue microenvironment to guide cellular localization.