For many years the treatment of multiple myeloma was limited to such regimens as melphalan-prednisone, high-dose dexamethasone, and vincristine-doxorubicin-dexamethasone (VAD). These combinations provided response rates of 45-55%, with complete remission rates of up to 10%. With the advent of thalidomide- and bortezomib-based combinations, response rates to induction therapy have risen to 85-95% in previously untreated patients and are associated with complete remission rates up to 25%. However, these agents are associated with such side-effects as somnolence, constipation and neuropathy. Lenalidomide, a thalidomide analog, was developed with the hope of improving both the efficacy and toxicity profile of thalidomide, and has subsequently shown significant clinical activity in patients with multiple myeloma. We describe the role of lenalidomide in patients with symptomatic multiple myeloma that is newly diagnosed, relapsed and/or refractory to other therapies, or concurrent with primary amyloidosis.