Lenalidomide, a novel immunomodulatory agent, was approved by the US Food and Drug Administration for the treatment of myelodysplastic syndrome and relapsed multiple myeloma. Data from preclinical studies paved the way for clinical trials of lenalidomide in mantle cell lymphoma (MCL). Initial phase I and II clinical trials of lenalidomide alone and as part of combination regimens in patients with relapsed/refractory MCL have shown promising results. Its immunomodulatory, T cell costimulatory, anti-inflammatory and anti-angiogenic actions working together in the tumor cell microenvironment seem to be responsible for its enhanced antitumor efficacy. Lenalidomide's nature of action and safety profile favor it over other agents studied in relapsed/refractory MCL. This review summarizes the data from preclinical and clinical studies of lenalidomide in relapsed/refractory MCL and compares the results with those of other novel agents being used for relapsed/refractory MCL.