The evolution of thalidomide as an effective treatment in several neoplasms has led to the search for compounds with increased antiangiogenic and anti-tumor effects, but decreased side-effects. The development of thalidomide analogues which retain the immunomodulatory effects of the parent compound, while minimizing the adverse reactions, brought about a class of agents termed the Immunomodulatory drugs (IMiDs). The IMiDs have undergone significant advances in recent years as evidenced by the recent FDA-approvals of one of the lead compounds, CC-5013 (lenalidomide), for 5q-myelodysplasia and for multiple myeloma (MM). Actimid (CC-4047), another IMiD lead compound, has also undergone clinical testing in MM. Apart from hematologic malignancies, these drugs are actively under investigation in solid tumor malignancies including prostate cancer, melanoma, and gliomas, in which potent activity has been demonstrated. The preclinical and clinical data relating to these analogues, as well as ENMD-0995, are reviewed herein. Encouraging results with these thalidomide analogues brought forth synthesis and screening of additional novel thalidomide analogues in the N-substituted and tetrafluorinated classes, including CPS11 and CPS49. This review also discusses the patents and preclinical findings for these agents.