The significant clinical activity of lenalidomide in relapsed CLL was first described several years ago. Since then the problems of tumor flare and tumor lysis have emerged, and upfront single agent studies have reported response rates that were perhaps a little disappointing. Interest in elucidating the place of lenalidomide in CLL therapy remains intense, however, and combination studies are in progress. As laboratory efforts start to provide more insight into the mechanisms of antitumor efficacy and tumor flare, rational strategies for combination therapy will soon follow.