The application of nucleoside analogue-based chemotherapy and immunotherapy with rituximab or alemtuzumab has increased both response rate and survival in patients with Chronic Lymphocytic Leukemia (CLL). However, because none of these therapies is curative, sequential therapeutic regimens are required. The majority of patients with relapsed or refractory CLL carry poor prognostic factors and show shorter overall survival and resistance to standard treatment. Numerous drugs have recently been approved for CLL therapy and many novel agents are under clinical investigation. The role of the tumor microenvironment and of immune dysfunction in CLL have allowed to enlarge the therapeutic armamentarium for CLL patients. This article will provide a comprehensive summary regarding mechanism of action, efficacy and safety of lenalidomide in CLL patients. Relevant clinical trials using lenalidomide alone or in combinations are discussed. Lenalidomide shows good activity also in relapsed/refractory or treatment-naive CLL patients. Definitive data from ongoing studies are needed to validate overall and progression-free survival. The toxicity profile might limit lenalidomide use because it can result in serious side effects, but largely controlled by gradual dose escalation. Further understanding of the exact mechanism of action in CLL will allow more efficacious use of lenalidomide alone or in combination regimens.