Lenalidomide (Revlimid) repairs and reverses cellular and humoral immune dysfunction in CLL. This agent enhances autologous T-cell immunologic synapse formation and functional activity (repairs impaired T-cell actin cytoskeletal signaling). NK-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CLL cells is enhanced by preincubation of NK cells with lenalidomide before exposure to rituximab-exposed CLL cells. Lenalidomide enhances APC function of CLL cells (up-regulation of costimulatory molecules). Exposure of drug increases functional surface CD154 expression on CLL cells, inducing a CD154 gene therapy activation phenotype. Importantly, lenalidomide-induced CD154-positive CLL cells promote antibody (IgM and IgG) production by normal B cells. The immunomodulatory effect of lenalidomide on stromal cells, nurse-like cells, and angiogenic status remains to be fully elucidated.