Mechanisms of action of lenalidomide in lymphoid malignancies. Direct antitumor effects primarily mediated by lenalidomide binding CRL4^CRBN, altering affinity for E3-ubiquitin ligase substrates. Lymphoid transcription factors IKZF1 (Ikaros) and IKZF3 (Aiolos) are preferentially ubiquitinated and degraded rapidly with lenalidomide, causing decreased NF-κB, decreased MYC and IRF4, increased p21^WAF1, and suppression of cell cycle via degradation of cyclin-dependent kinases. There is also increased interferon production via decreased IRF4 (suppresses IFN response), which promotes cellular death. Other CRL4^CRBN substrates may be affected, but are less defined. Immunomodulatory properties: Improvement in T-cell and NK-cell antitumor activity is seen with lenalidomide, including IL-2–driven costimulation of T cells (via increased degradation of IKZF1 and IKZF3 in T cells). Regulatory T cells are suppressed and there is a skewing toward Th1 population with lenalidomide. The NK- and T-cell effects of lenalidomide in lymphoma are synergistically enhanced with rituximab in preclinical studies. Anti-angiogenic properties: lenalidomide decreases angiogenesis in part via decreased microvessel density and it inhibits tumor growth and dissemination of disease through depletion of monocytes and macrophages associated with lymphangiogenesis. ADCC, antibody-dependent cell-directed cytotoxicity; Cdc42, cell division control protein 42; CLL, chronic lymphocytic leukemia; CRL4^CRBN, Cullen 4 ring-E3 ubiquitin ligase–cereblon complex; FL, follicular lymphoma; His H3-Me, histone H3 methylation; ICAM-1, intercellular adhesion molecule 1; IFN, interferon; IKZF1, Ikaros; IKZF3, Aiolos; IRF4, interferon regulatory factor 4; LFA-1, lymphocyte function–associated antigen 1; MHC, major histocompatibility complex; TCR, T-cell receptor; WASp, Wiskott-Aldrich syndrome protein.