Following the discovery of its anti-angiogenic properties and despite its tragic history, thalidomide has re-surfaced in the field of oncology. Concurrent with its evaluation in various clinical trials for cancer, thalidomide's mechanism of action is sought and new analogues with improved efficacy and pharmacological profile are emerging. This review is a critical evaluation of thalidomide metabolism, molecular targets, anti-angiogenic activity and clinical efficacy with an emphasis on metastatic prostate cancer.