A new agent that is being used in chronic lymphocytic leukemia (CLL) and is receiving considerable interest is the immunomodulatory drug lenalidomide. The precise anti-CLL mechanism of action of lenalidomide is not yet completely defined. In this perspective article, Drs. Ramsay and Gribben examine the multiple biological effects of lenalidomide on various cell targets that likely contribute to its anti-CLL activity. See related paper on page 1266.