Thalidomide is emerging as a potentially important therapeutic option in the treatment of metastatic prostate cancer. Although the mechanism of action of this agent remains elusive in malignancies of the prostate, recent data has indicated that thalidomide may play a role in inflammation, immunomodulation, and anti-angiogenesis. Lenalidomide (CC-5013), a thalidomide analogue with improved activity and safety profile in certain disease contexts, is in the early stages of development in prostate cancer. This review will provide the current status of the history, mechanism, metabolism, and clinical use of thalidomide in metastatic prostate cancer. It will also describe the mechanism and clinical use of lenalidomide as it pertains to malignancies of the prostate.