Recently, it has been demonstrated that a number of novel thalidomide analogs possess anti-cancer properties due to their T cell co-stimulatory, anti-angiogenic and/or anti-inflammatory effects. Based on such effects, a class of thalidomide analogs known as Immunomodulatory Drugs (IMiDs) have recently entered into phase I clinical trials for the treatment of a number of cancers. The lead IMiD CC-5013 (referred to clinically as REVIMID) is now entering phase III clinical trials for multiple myeloma and metastatic melanoma, while CC-4047 (ACTIMID) is currently under investigation in phase I/II and II trials for multiple myeloma and prostate cancer, respectively. The other group of compounds, classified as Selective Cytokine Inhibitory Drugs (SelCIDs), do not co-stimulate T cells, but have anti-inflammatory and anti-angiogenic properties. Moreover, a subset of SelCIDs has been found to possess direct anti-tumor activity both in vitro and in vivo. This minireview highlights the various mechanisms of action associated with these compounds and their subsequent clinical development. The enhanced efficacy and lower side-effect profiles of the analogs in comparison to thalidomide make the use of these agents very attractive as novel anti-cancer agents.