Microvessel density is a prognostic factor for many cancers, including prostate. For this reason, several studies and therapeutic approaches that target the tumor microvasculature have been attempted. Thalidomide has long been recognized as an antiangiogenic molecule. Recently, this drug has regained favor as an anticancer agent and is in clinical trial for multiple myeloma and prostate cancer, among others. This article will briefly review the proposed mechanisms of action for thalidomide, discuss why these activities are of therapeutic value in diseases currently undergoing clinical trials, and summarize the current status of clinical trials for prostate cancer. The focus will be predominantly on the relationship of thalidomide to angiogenesis, as well as on the future and potential value of thalidomide-inspired structural derivatives.