Lenalidomide is a member of the immunomodulatory agents (IMiDs), and is currently approved for use in myelodysplastic syndromes and multiple myeloma. In chronic lymphocytic leukemia (CLL), lenalidomide has anti-tumor activity which appears distinct, both mechanistically and clinically, from that observed in the approved indications. Furthermore, lenalidomide leads to toxicities, such as tumor flare reaction and tumor lysis, even at low dosing, that is not anticipated with lenalidomide therapy in other disorders. This review will discuss the current understanding of the mechanisms of action of lenalidomide in CLL, lessons of administration learned from clinical trials in CLL to date, and the potential role of lenalidomide in CLL for the future.