Lenalidomide is an immunomodulatory drug (IMiD), which is well established and approved in the treatment of multiple myeloma (MM) and 5q-myelodysplastic syndrome (MDS). The mode of action includes immune modulation, anti-angiogenetic, anti-inflammatory, and anti-proliferative effects. Development of lenalidomide initiated a profound shift in therapeutic approaches especially toward MM. This chapter will discuss the mode of action of lenalidomide as well as its clinical applications. Important clinical phase II and III data of lenalidomide are presented. Currently, lenalidomide is not only investigated in MM and MDS, but also in malignant lymphomas and other entities.