Multiple chemokines are made in the thymus, and they are likely to function in the fine control of cellular migration and regulation of thymic T cell development. Mice lacking the gene mel-18, a member of the mammalian Polycomb group genes, displayed impaired thymic T cell development. Here we report that expression of chemokine receptors CXCR4 and CCR9 are regulated by mel-18 and that CXCL12/SDF-1- and CCL25/TECK-mediated chemotactic activities are also affected by the loss of mel-18. In mel-18-/- mice, high expression of CXCR4 on CD4-CD8- cells might lead to trapping in the SDF-1 rich subcapsular region, while low expression of CCR9 on CD4+CD8+ cells might reduce cell migration to the medulla. Therefore, this member of the Polycomb group genes plays a role in thymic T cell migration and differentiation via the chemokine system.