Introduction: Lenalidomide is an immunomodulatory drug (IMiD) with a unique mode of action (MOA) that may vary across disease-type. It is currently approved in multiple myeloma (MM), myelodysplastic syndrome (MDS) and mantle cell lymphoma (MCL), yet is also clinically active in a host of lymphoproliferative diseases, including chronic lymphocytic leukemia (CLL). Due to its protean effects on the immune system, lenalidomide may be particularly appealing in CLL, which is distinct in its ability to evade immune recognition and cause immunosuppression.Areas covered: This review recaps the biological mechanisms of lenalidomide specific for CLL, and summarizes the clinical data in previously untreated and relapsed/refractory (R/R) CLL patients, with emphasis on toxicity. Moreover, lenalidomide treatment is put into the context of the highly effective targeted agents that are drastically changing the therapeutic approach in CLL.Expert opinion: Lenalidomide is a potent drug in CLL, both in first line and relapse. However, in comparison to other newly available agents, lenalidomide has slow onset of efficacy and notable toxicity profile that limits both its single agent use and combinations with chemotherapy. Future trials will hopefully direct our ability to harness lenalidomide MOA to best incorporate it in the rapidly evolving landscape of CLL treatment.