The mechanistic data we present further elucidate the immunomodulatory mechanism of action of lenalidomide to include abrogation of the CXCL12–CXCR4-mediated IL-10 response by CLL cells and prevention of T-cell suppression due to IL-10-induced phosphorylation of Y705-STAT3. Here, STAT3 is linked to B-cell chronic lymphocytic leukemia.