The clinical development of lenalidomide (Revlimid™), then pomalidomide (Actimid™) as members of immunomodulatory drugs (IMiDs) for the treatment of multiple myeloma (MM), exemplifies how insight into disease biology can lead to design of effective therapeutic agents. Increased experience and understanding of IMiD's diverse biological effects has lead to rational design of lenalidomide-based treatment-regimens over recent years. However, much about lenalidomide is yet to be understood and fully exploited. Here, we review what is known of lenalidomide's biological effects, clinical certainties and uncertainties in the treatment of MM, and explore its future potential with other synergistic therapeutic agents. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc.