Leukocyte trafficking, which is critically regulated by chemokines and their receptors, shares many of the characteristics of tumor cell infiltration and metastasis. Expression of CC chemokine receptor 4 (CCR4) by tumor cells is associated with skin involvement, but CCR4 also has an important role in normal and tumor immunity. In a subset of patients with CCR4+ T-cell leukemia/lymphoma, the tumor cells themselves function as regulatory T (Treg) cells, contributing to tumor survival in the face of host antitumor immune responses. In other types of cancers, the chemokines TARC/CCL17 and MDC/CCL22, specific ligands for CCR4 that are produced by tumor cells and the tumor microenvironment, attract CCR4+ Treg cells to the tumor, where they create a favorable environment for tumor escape from host immune responses. A novel humanized anti-CCR4 monoclonal antibody (mAb) has been developed, the Fc region of which is defucosylated to enhance antibody-dependent cellular cytotoxicity by increasing its binding affinity to Fc receptor on effector cells. We are now conducting a phase I clinical trial of this anti-CCR4 mAb in patients with CCR4+ T-cell leukemia/lymphoma in Japan (clinical trials gov. identifier: NCT00355472). Anti-CCR4 mAb could be an ideal treatment modality for many different cancers, not only to directly kill the CCR4+ tumor cells, but also to overcome the suppressive effect of CCR4+ Treg cells on the host immune response to tumor cells. (Cancer Sci 2006; 97: 1139–1146)